What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

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Immunotherapy safe for patients with COVID-19, cancer

https://medicalxpress.com/news/2020-07- ... ancer.html

Preliminary data from researchers at the University of Cincinnati Cancer Center show that immunotherapy doesn't necessarily worsen complications for patients with both COVID-19 and cancer.

This data is being presented by Layne Weatherford, Ph.D., UC postdoctoral fellow, at the American Association for Cancer Research Virtual Meeting: COVID-19 and Cancer, Monday, July 20.

Weatherford works in the lab of Trisha Wise-Draper, Ph.D., an associate professor of medicine, Division of Hematology Oncology, at the UC College of Medicine, UC Health oncologist and medical director of the UC Cancer Center Clinical Trials Office.

"Many COVID-19 complications result from an overactive immune response, leading to an increased production of proteins called cytokines," Weatherford says. "Increased production of these proteins can cause issues like respiratory failure. Patients with cancer are more susceptible to COVID-19 infection as well as severe complications from it.

"Many patients with cancer are treated with immunotherapy, which activates the immune system against cancer to destroy it. In patients with both COVID-19 and cancer, our team thought that immunotherapy might increase the immune system response, which could already be overactive because of the COVID-19 infection."

Wise-Draper says researchers thought treating COVID-19 patients with cancer immunotherapy might result in worsening patients' health and overall outcomes.

"We are continuing to investigate whether immunotherapy causes an increased production of these proteins by immune cells from COVID-19 patients, but our initial findings are showing that immunotherapy is not significantly impacting it," she adds.

Researchers are conducting this study using blood samples from patients with cancer taken from the UC COVID-19 biorepository, which Kris Hudock, MD, assistant professor in the Division of Pulmonary, Critical Care and Sleep Medicine at the UC College of Medicine, oversees.

"We are examining how immune checkpoint inhibitors, drugs that allow immune cells to respond more strongly, in combination with other treatments, like chemotherapy or radiation, affect the immune cells of COVID-19 patients and patients with both COVID-19 and cancer," she says.

She and Weatherford add that their preliminary data show that an anti-diabetic drug, metformin, can reduce production of these proteins by immune cells of COVID-19 patients.

"These are promising, initial findings," Wise-Draper says. "Additional research is needed, but our results show that we might be able to treat COVID-19 complications with metformin or a similar drug one day."
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Flipping a Metabolic Switch to Slow Tumor Growth

https://ucsdnews.ucsd.edu/pressrelease/metabolicswitch

The enzyme serine palmitoyl-transferase can be used as a metabolically responsive “switch” that decreases tumor growth, according to a new study by a team of San Diego scientists, who published their findings Aug. 12 in the journal Nature.

By restricting the dietary amino acids serine and glycine, or pharmacologically targeting the serine synthesis enzyme phosphoglycerate dehydrogenase, the team induced tumor cells to produce a toxic lipid that slows cancer progression in mice. Further research is needed to determine how this approach might be translated to patients.

Over the last decade researchers have learned that removing the amino acids serine and glycine from animal diets slows the growth of some tumors. However, most research teams have focused on how these diets impact epigenetics, DNA metabolism, and antioxidant activity. In contrast, the researchers from the University of California San Diego and the Salk Institute for Biological Studies identified a dramatic impact of these interventions on tumor lipids, particularly those found on the surface of cells.

"Our work highlights the beautiful complexity of metabolism as well as the importance of understanding physiology across diverse biochemical pathways when considering such metabolic therapies," said Christian Metallo, a professor of bioengineering at the Jacobs School of Engineering at UC San Diego and the paper’s corresponding author.

In this case, serine metabolism was the researchers’s focus. The enzyme serine palmitoyl-transferase, or SPT, typically uses serine to make fatty molecules called sphingolipids, which are essential for cell function. But if serine levels are low, the enzyme can act “promiscuously” and use a different amino acid such as alanine, which results in the production of toxic deoxysphingolipids.

The team decided on this research direction after examining the affinity that certain enzymes have to serine and comparing them to the concentration of serine in tumors. These levels are known as Km or the Michaelis constant, and the numbers pointed to SPT and sphingolipids.

"By linking serine restriction to sphingolipid metabolism, this finding may enable clinical scientists to better identify which patients’ tumors are most sensitive to serine-targeting therapies," Metallo said.

These toxic deoxysphingolipids are most potent at decreasing the growth of cells in "anchorage-independent" conditions—a situation where cells cannot easily adhere to surfaces that better mimics tumor growth in the body. Further studies are necessary to better understand the mechanisms through which deoxysphingolipids are toxic to cancer cells and what effects they have on the nervous system.

In the Nature study, the research team fed a diet low on serine and glycine to xenograft model mice. They observed that SPT turned to alanine to produce toxic deoxysphingolipids instead of normal sphingolipids. In addition, researchers used the amino-acid based antibiotic myriocin to inhibit SPT and deoxysphingolipid synthesis in mice fed low serine and glycine diets and found that tumor growth was improved.

Depriving an organism of serine for long periods of time leads to neuropathy and eye disease, Metallo pointed out. Last year, he co-lead an international team that identified reduced levels of serine and accumulation of deoxysphingolipids as a key driver of a rare macular disease called macular telangiectasia type 2, or MacTel. The work was published in the New England Journal of Medicine. However, serine restriction or drug treatments for tumor therapy would not require the prolonged treatments that induce neuropathy in animals or age-related diseases.

This work was supported by the National Institutes of Health (R01CA188652 and R01CA234245; U54CA132379), a Camille and Henry Dreyfus Teacher-Scholar Award, the National Science Foundation Faculty Early Career Development (CAREER) Program, the Helmsley Center for Genomic Medicine and funding from Ferring Foundation. This work was also supported by NIH grants to the Salk Institute Mass Spectrometry Core (P30CA014195, S10OD021815).

Serine restriction alters sphingolipid diversity to constrain tumour growth

https://doi.org/10.1038/s41586-020-2609-x
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Improve outcomes for TIL therapies by tackling process challenges

https://www.fiercebiotech.com/sponsored ... challenges

Introduction


Adoptive cell transfer, in which a patient’s own immune defenses are boosted or rewired to kill cancer cells, is one of the most effective forms of personalized cancer care to ever reach patients. There are two types of adoptive cell transfer. In one type, immune cells called T cells are isolated, genetically modified, expanded, and returned to patients (e.g., CAR T cell therapy, TCR-modified T cell therapy). In the second type, the cells are expanded and infused back without genetic modification. The latter involves tumor-infiltrating lymphocytes or TILs – a naturally occurring, heterogeneous population of white blood cells that migrate into a tumor. TILs are known to be the most suitable immune cells to attack and destroy the cancer they homed in on.

“Back in 1988, we published our first work showing that TILs isolated from patients with metastatic melanoma could be expanded in the lab and returned to the patient, where they mediated cancer regression,” stated Dr. Steven Rosenberg, chief of surgery at the U.S. National Cancer Institute, in a report by the American Association of Cancer Research (AACR) in 2018 (1). His decades-long research into TILs, along with multiple studies by other groups, have proven that TIL therapy shows significant, durable success in treating melanoma (2, 3). TIL therapy is now being explored for precision treatment of other types of solid cancers.

While it has been advanced over many years, the process of developing TIL therapies still suffers from certain challenges, particularly in the collection and processing of tumor samples used to extract TILs. This article attempts to lay bare some of these challenges and discuss how novel technological solutions can help overcome them.

Collecting tumor tissue for TIL therapies

TILs are typically not present in high numbers within a tumor. Thus, they must be carefully extracted and handled to ensure that cell viability and yield is maintained. The first step in preparing TILs for therapeutics purposes is the collection of a sample of the solid tumor tissue. Dr. Sophie Papa, a Clinical Reader in immuno-oncology and Consultant Medical Oncologist at King’s College London, is a medical lead heavily involved in various clinical trials on TIL therapies. She says that “one of the greatest factors currently preventing patients from receiving TIL therapy is the difficulty of easily accessing and harvesting their tumors as a sample for processing.” The reason, she elaborates, is the labor-intensive protocols that require skilled personnel like surgeons and technicians who can expertly remove enough viable tissue.

After the tissue is taken in the operating room, it is sent to the pathology department. There, a pathologist decides how much of it can be allocated to research while keeping enough material for clinical and diagnostic needs. “Only pathologists can make this decision – they need to make sure that they do not harm the clinical output of the patient,” says Dr. Yehudit Cohen, Scientific Director of MIDGAM – the Israel National Biobank for Research, a governmental entity located at the Weizmann Institute for Science in Israel. Once the tissue is released by the pathologist, Dr. Cohen helps direct it to researchers for further research and processing.

Maintaining cell viability for higher yields

According to Dr. Cohen, the time between tissue resection and tissue submersion in the required medium (and the choice of medium itself) plays a significant role in cell viability and yield. “We measure this time length in two portions – the warm and the cold ischemic time,” explains Dr. Cohen. “We can only affect the cold ischemic time. The warm ischemic time [the time a tissue remains at the original body temperature after its blood supply has been cut off, but before it is cooled] depends on operation room procedures. For example, we can ask for the tissue to be delivered to us as soon as possible, but if the surgeon is still working and is not able to release the tissue, we can’t really change that.”

However, once the tissue is out of the operation room on ice, it must quickly arrive at the pathology department, where it is cut up and allocated for research and clinical purposes. There is some control over this ‘cold ischemic time’ to influence cell viability of the tissue given to a TIL therapy study. “The quality and viability of the tissue is dependent on how quickly it's cut up, how well its temperature is controlled, and how rapidly it's put into the medium that it's transported or disaggregated in,” Dr. Papa confirms. All of these steps introduce variability to the quality of the starting material, and, in the end, to the TIL therapy.

The viability of cells in the tissue sample is also affected by the donor's clinical condition. For instance, following chemo or radiotherapy procedures given to the patient, many cells may be necrotic, fibrotic and/or nonviable. Likewise, the type of tumor that is sampled can also impact the cell yield. “If you take colon or lung tumor tissues, you will probably have enough material to work with,” Dr. Cohen states. “But in contrast, most tumoral breast tissues are small – so, the potential of having enough tissue to work with is lower. Another example is pancreatic cancer. It’s very hard to access the tumor in a procedure like a biopsy – so collecting enough tissue is difficult, on top of the fact that TILs are present in low numbers.” Dr. Papa adds that some cancers have more lymphocytes infiltrating them than others, and these differences are inherently part of the biology of the disease.

At the National Center for Cancer Immune Therapy, University Hospital Herlev in Denmark, researchers have access to fresh tissue when isolating TILs for therapeutic purposes. “In our facility, we don't have to get chilled tissue from other parts of Denmark, because we usually have the patients in-house or in a nearby hospital,” explains Dr. Özcan Met, Associate Professor and Head of Cell Manufacturing at the center. Dr. Met’s team is able to expand TILs from resected tumor in more than 95% of patients with metastatic melanoma. He believes this is, at least, partly due to their rapid access to fresh tissue.

Improving manufacturing – automation, environmental control, and standardization

Experts like Drs. Papa, Cohen, and Met agree that there is a lot of room to improve the efficiency of the TIL therapy development process. Particularly, in the time period between physically removing tissue from a patient and transporting it to the laboratory – whether that's in the same building or on a different continent – several aspects can be optimized to enhance the quality and efficiency of the process.

Anything that involves the patient is hard to standardize. “Harvesting the tissue and treating the patient are two things that you can't standardize or automate at either end, but everything else in the middle we should be striving to automate and standardize as much as possible,” Dr. Papa suggests. Also, she believes that eliminating the need for a surgical procedure, where possible, would be helpful. Interventional radiology and biopsy-based techniques to obtain tissue are much less complex than surgery and would speed up the process. According to Dr. Papa, technologies that could enable rapid tissue disaggregation, maybe directly at the bedside or in the operating theater, would improve the quality of the harvest.

Once the samples are received in the lab, they are taken into a sterile environment where the tumor is disaggregated and the cells grown and expanded in medium supplemented with growth factors, cytokines (e.g., high dose of IL-2), and supporting feeder cells. Throughout this manufacturing process, there are multiple quality checkpoints for the cells, but much of the process is not standardized or temperature controlled.

According to Dr. Papa, there are many different protocols using various reagents and supporting cells for different periods of culture. “Traditionally, and in some current circumstances, a lot of this is done in a manual, open manner,” she notes. Such open systems lack effective monitoring of the process temperature, which can result in low yields, contamination, and inconsistencies between samples. Moreover, the tumors used to extract TILs may contain contaminants from the beginning.

Right now, one of the biggest hurdles in trials of TIL therapies is the lack of standardization of protocols, whether it’s in sample collection or processing. “If you've got multiple different centers that are recruiting to your trial, the more standardized things are, the more you can compare results, like whether patients respond to treatments or not, and be confident about the quality of the cellular product,” Dr. Papa says. Her recommendation to reduce variability is to make the upstream process of getting tumor samples for the therapy manufacturer as simple, automated, standardized, and regulated as possible.

Dr. Met agrees that there should be more standardization and optimization in the upstream steps. He explains that TIL therapy is a very specialist form of therapy, and different countries have different regulations for manufacture. “For instance, in Denmark, we can use allogeneic feeder cells for the expansion of the TILs, but this is not allowed in some other countries and they have to use autologous feeder cells,” Dr. Met adds, pointing out that changing manufacturing protocols requires extensive validation, which is both costly and time-consuming. He believes there’s more leeway to optimize sample processing before expansion, and industry could help in this regard with collaborations and new technological innovations.

“It would be really helpful to have more sharing of information relevant to sample processing, so that there can be more standardization across protocols,” concludes Dr. Papa. “That way, we can draw conclusions more confidently across trials about the efficacy and feasibility of the therapy.”

References

Olsen K. TIL therapy explained by Steven Rosenberg, MD, PhD. AACR. November 2018. Accessed July 6, 2020.
Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319(25):1676‐1680. doi: 0.1056/NEJM198812223192527
Met Ö, Jensen KM, Chamberlain CA, Donia M, Svane IM. Principles of adoptive T cell therapy in cancer. Semin Immunopathol. 2019;41:49-58. doi: 10.1007/s00281-018-0703-z
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Liver dysfunction is associated with poor prognosis in patients after immune checkpoint inhibitor therapy

https://www.nature.com/articles/s41598-020-71561-2

Abstract

Immune-related adverse events (irAEs) are induced by immune checkpoint inhibitors (ICIs). Liver is one of the main target organs which irAEs occur and we investigated the influence of liver dysfunction on prognosis of patients after ICIs. From July 2014 to December 2018, 188 patients with diverse cancers who received ICIs (nivolumab or pembrolizumab) were enrolled. Twenty-nine patients experienced liver dysfunction of any grades after ICIs. Progression-free survival (PFS) was significantly shorter in the liver dysfunction-positive group than in the liver dysfunction-negative group, and a similar result was obtained for Overall survival (OS). Multiple logistic regression analysis revealed liver metastasis and alanine aminotransferase before ICIs were associated with a higher incidence of liver dysfunction after ICIs. Regardless of liver metastasis, PFS and OS were significantly shorter in the liver dysfunction-positive group. In conclusion, this study suggests liver dysfunction is associated with poor prognosis in patients after ICIs with diverse cancers.

Introduction

Cancer was the second most common cause of death in the last decade, and was responsible for an estimated 9.6 million deaths worldwide in 20181. Cancer is treated by surgical resection, radiation and chemotherapy, but the mortality rate in cancer patients is still high. Therefore, new strategies to treat cancer are needed.

Recently, immunotherapy has become a mainstay of treatment of cancer. Antibodies against cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) and its ligands (PD-L1/PD-L2) can modulate the immune response to cancer clearance in a various human malignancies. The PD-1 pathway operates in the tumor microenvironment, unlike CTLA-4, which mainly works in the lymph nodes2. PD-1 interacts with its ligands on the surface of tumor cells and tumor-associated macrophages, dendritic cells, fibroblasts, and activated T cells in the immune milieu3,4,5,6 . The binding of PD-1 with its ligands block antitumor activity of T cell7,8,9. Nivolumab and pembrolizumab are fully humanized immunoglobulin G4 PD-1 immune checkpoint inhibitor (ICI) antibodies that selectively block the interaction of the PD-1 receptor and its ligands10,11. These inhibitors have significant clinical activity and have improved prognosis in multiple cancer types, including non-small-cell lung cancer, renal cell carcinoma, urothelial carcinoma, gastric cancer, head and neck squamous cell carcinoma, malignant melanoma, and hepatocellular carcinoma11,12,13,14,15,16,17,18,19,20,21.

Blocking immunosuppressive ligand receptor interactions enhances the anticancer effects of lymphocytes. However, these molecules are also involved in healthy immune tolerance, and therefore adverse reactions to self-antigens can occur. The adverse events caused by autoimmune reactions are currently denoted as immune-related adverse events (irAEs) to differentiate them from idiosyncratic drug-induced organ damage 22.

Most patients with irAEs can be managed, but some patients treated with ICIs have died because of irAEs23. Conversely, some patients treated with ICIs who develop irAEs have higher autoimmune responses and the drugs have higher efficacy24,25,26. Therefore, irAEs are a major problem with ICI therapies, and the influence of irAEs in patients receiving ICI therapies is unclear.

The liver is one of the organs that potentially manifests irAEs, and it was reported that immune-mediated liver dysfunction of any grade occurs in 1–8% of patients with PD-1 inhibitors27,28,29. There is no report on association between liver dysfunction due to irAE and prognosis in patients treated with ICIs.

In this multicenter retrospective cohort study of patients treated with ICI monotherapy for diverse cancers, we investigated the influence of liver dysfunction on prognosis in patients after ICI treatment.

Patient characteristics

We included 188 patients with advanced cancer treated with ICIs monotherapy (nivolumab or pembrolizumab) (Fig. 1A). There were no patients treated with ICI combination therapy. The baseline clinical characteristics for the study cohort at initiation of ICIs are summarized in Table 1. The majority of patients (72.9%) were over 65 years old. Fifty-five patients (29.3%) had liver diseases; most were in the remission phase of HBV infection, and their liver functions before ICIs were normal. Thirty patients (16.0%) had liver metastases before the initiation of ICIs and their liver functions were also normal before initiation of ICIs. ICIs were selected as second-line or later-line treatments in the majority of patients. However, 13 patients (6.4%; 12 non-small cell lung cancer patients and 1 urothelial carcinoma patient) received ICIs as first-line treatment. Only 4 patients (2.1%) had been previously treated with ICIs.

Frequency and severity of liver dysfunction

Twenty-nine of 188 (15.4%) patients developed liver dysfunction of any grade after ICIs (Table 2). Seventeen percent of patients treated with nivolumab developed liver dysfunction and 13% of patients treated with pembrolizumab developed liver dysfunction. Ten patients (5.3%) required the interruption of ICIs (dose delay, cessation, or therapeutic intervention for immunosuppressive therapy) due to grade 2 or more of liver dysfunction after ICIs. The frequency of interruption due to severe liver dysfunction in patients treated with pembrolizumab (9.8%) was higher than that in patients treated with nivolumab (3.1%). The median time to onset of liver dysfunction after ICIs was 43 days (range 7–210 days) (Fig. 1B). Most cases of liver dysfunction occurred within 3 months of the initiation of the ICI therapy, although five cases occurred more than half a year after initiation.

Prognosis of patients treated with ICIs

We compared the prognosis of patients with liver dysfunction (positive group) and without liver dysfunction (negative group). The Progression-free survival (PFS) in the positive group (median 64 days, 95% CI 28–110 days) was significantly shorter than that in the negative group (median: 121 days, 95% CI 89–178 days) (Fig. 2A). Additionally, the Overall survival (OS) in the positive group (median 184 days, 95% CI 126–316 days) was significantly shorter than that in the negative group (median: 427 days, 95% CI 328–548 days) (Fig. 2B). We further subdivided patients in the positive group based on time to liver dysfunction: patients who developed liver dysfunction within 30 days after ICI therapy were defined as the early onset group, and patients who developed liver dysfunction more than 30 days after ICI therapy were defined as the late onset group. The PFS in the early onset group (median 21 days, 95% CI 1–44 days) was significantly shorter than that in the late onset group (median: 93 days, 95% CI 33–186 days) (Fig. 2C). The OS in the early onset group (median 76 days, 95% CI 25–223 days) was also significantly shorter than that in the late onset group (median: 263 days, 95% CI 141–358 days) (Fig. 2D). In conclusion, the PFS and OS of the positive group were significantly shorter than those of the negative group, and among patient with liver dysfunction, those with early onset had a worse prognosis than those with late onset.

Predictive factors of liver dysfunction after ICIs

We investigated which factors were associated with liver dysfunction after ICI. For univariate screening, univariate analyses were performed and then those risk factors deemed to have a statistically significant association with the outcome in the univariate analyses were then included in the multiple logistic regression model. Baseline clinical characteristics between the positive group and the negative group were compared. In univariate analysis, there were significant differences in liver metastasis (p = 0.0014), hemoglobin (p = 0.0439), and alanine aminotransferase (ALT) (p = 0.0085) (Table 3A). Multiple logistic regression analysis revealed that liver metastasis (OR 3.24, 95% CI 1.27–8.30, p = 0.0161) and ALT (> 13 IU/L vs ≤ 13 IU/L; OR 2.54, 95% CI 1.08–5.96, p = 0.0294) before ICIs were significantly associated with a higher incidence of liver dysfunction after ICIs (Table 3B).

Influence of liver dysfunction after ICIs on prognosis based on liver metastasis


Next, the effect of liver dysfunction on the prognosis of patients with liver metastasis was investigated. Among patients with liver metastasis, the PFS of patients with liver dysfunction (median 33 days, 95% CI 21–112 days) was shorter than that of patients without liver dysfunction (median: 67 days, 95% CI 28–200 days) (Fig. 3A). The OS of patients with liver dysfunction (median 141 days, 95% CI 45–220 days) was also shorter than that of patients without liver dysfunction (median: 242 days, 95% CI 65–421 days) (Fig. 3B). Similar results were observed among patients without liver metastasis. Among patients without liver metastasis, the PFS of patients with liver dysfunction (median: 75 days, 95% CI 28–112 days) was shorter than that of patients without liver dysfunction (median: 122 days, 95% CI 98–201 days) (Fig. 3C). The OS of patients with liver dysfunction was also significantly shorter (median 281 days, 95% CI 126–384 days) than that of patients without liver dysfunction (median: 492 days, 95% CI 339–620 days) (Fig. 3D). These results indicated that the prognosis of patients with liver dysfunction was poor regardless of liver metastasis.

Influence of liver dysfunction after ICIs on prognosis of patients without treatment interruption


There were 10 patients who required interruption of ICI treatment (dose delay, cessation, or therapeutic intervention for immunosuppressive therapy) due to grade 2 or more liver dysfunction. No patient died of liver failure. Based on the guidelines for liver dysfunction in the CTCAE 4.0, when patients had grade 1 liver dysfunction after ICIs, treatment could be continued with close monitoring. Therefore, the prognoses of patients with liver dysfunction who continued ICI treatment were studied. Among patients who did not experienced interruption of ICIs, the PFS of patients with liver dysfunction (median 56 days, 95% CI 28–112 days) was shorter than that of patients without liver dysfunction (median: 121 days, 95% CI 89–178 days) (Fig. 3E). Similarly, the OS of patients with liver dysfunction was significantly shorter (median 148 days, 95% CI 87–358 days) than that of patients without liver dysfunction (median: 427 days, 95% CI 328–548 days) (Fig. 3F). Therefore, the prognosis of patients who experienced liver dysfunction after ICIs was poor regardless of whether they had to discontinue ICIs.

Discussion

Although, there are several reports on predictors of irAEs after ICI therapy30,31, no report has focused on liver dysfunction. This study is the first report to reveal that liver metastasis before ICI therapy is a predictive factor for liver dysfunction after ICI therapy. The frequency of liver dysfunction after ICI therapy was higher in patients with liver metastases than in patients without liver metastases, and the odds ratio was 3.24 (95% CI 1.27–8.30). We also found that, among patients without liver metastases, the prognosis of patients with liver dysfunction after ICI therapy was clearly worse than that of patients without liver dysfunction. Therefore, patients with liver dysfunction after ICI therapy have poorer prognosis than patients without liver dysfunction.

The precise pathophysiology underlying immune-related adverse events is unknown but is believed to be related to the role that immune checkpoints play in maintaining immunologic homeostasis. As liver dysfunction after ICI therapy cannot be explained by any of the four mechanisms of irAE development, we have identified four potential mechanisms for liver dysfunction after ICI therapy. The first is increased T cell activity against antigens that are present in tumors and healthy tissue. This type of liver dysfunction is thought to be the most common type of irAE. The second is increased levels of preexisting autoantibodies32. This type of liver dysfunction is caused by autoimmune toxicities and includes neuromuscular dysfunction, Guillain–Barre syndrome, autoimmune thyroiditis, and acute presentation of AIH. The third is drug–induced liver injury. This type is due to immune-mediated or hypersensitive drug reaction or exposure to toxic doses of ICIs. The fourth potential mechanism is liver metastasis. This type sometimes occurs due to tumor progression even if the patient receives ICIs.

Previous studies have reported frequencies of all-grade and grade 3–4 liver dysfunction of 1.0–7.6% and 0.5–2.3%, respectively, in patients treated with nivolumab for malignant melanoma27,28. In a phase II/III trial of patients treated with pembrolizumab for non-small cell lung cancer, the frequency of all-grade liver dysfunction was 2.0–4.7%, and that of grade 3 or 4 liver dysfunction was 0.3–0.6%29. In this study, liver dysfunction of any grade after ICI monotherapy occurred in more than 15% of patients. Furthermore, 5.3% of patients required interruption of ICI monotherapy due to grade 3 or 4 severe liver dysfunction. We believe that the high frequency of liver dysfunction after ICI therapy in this study was caused by including not only irAE but also other types such as drug–induced liver injury. Liver biopsy will be required to determine the type of liver dysfunction in patients treated with ICIs.

The PFS and OS in patients who developed early-onset liver dysfunction were significantly shorter than those with late-onset liver dysfunction in our study. There are many reports about the relationship between the onset time of the irAE and prognosis33,34,35. Cortellini et al. reported that the early onset of liver dysfunction might be considered a treatment-related effect of cytokine release syndrome or hypersensitivity to the drug34. Another report suggests that the unidentified immune activity in the tumor may enhanced the effect of nivolumab in the early phase, which results in T cell recognition and activity against antigens in healthy tissues provide improving treatment with ICIs and important clues on the mechanism of PD-1-mediated toxicity and antitumor efficacy35. Further research is required to elucidate the mechanisms driving these associations.

This study suggests that liver dysfunction is associated with poor prognoses of patients receiving ICI therapy against multiple cancer types. There might be a selection bias in patient selection and collecting the patient information, because this study was retrospective with a small number of non-randomized, medical record-based cases. Therefore, in order to further clarify the influence of liver dysfunction after ICI therapy on the prognosis of patients with ICI therapy, it is necessary to continue to accumulate more cases and investigate these questions prospectively.

Methods
Accordance and guideline

All procedures performed in this study were in accordance with the ethical standards of the institution and ethical guideline for medical and human subject in Japan and with the 1964 Helsinki declaration and its later amendments.

Study design and participants

One hundred and eighty-eight patients with advanced-stage cancer (95 non-small cell lung cancer patients, 38 urothelial carcinoma patients, 28 gastric cancer patients and 27 renal cell carcinoma patients) treated with ICIs at two study centers (Osaka Medical College Hospital and Hokusetsu General Hospital) from July 2014 to December 2018 were enrolled in this study. All patients were treated with nivolumab or pembrolizumab monotherapy. We retrospectively collected the following patient data from medical records: age, sex, weight, stage of cancer, the number of previous chemotherapy lines, and laboratory data before the initiation of ICI therapy. ICIs induce various adverse events, which are graded according to the Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE 4.0), a tool commonly used for the evaluation of adverse events of chemotherapy. We treated adverse events according to the clinical guidelines of the American Society of Clinical Oncology36. We used these data to investigate the influence of liver dysfunction on prognosis in these patients after ICI therapy.

Statistical analysis

PFS was calculated as the time from the initiation of ICI therapy until tumor progression as determined by the treating physician, death from any cause, or last follow-up, whichever occurred first. OS was calculated from the time of the initiation of ICI therapy until death from any cause or last follow-up. We used the Kaplan–Meier method and log-rank test to compare the prognosis (PFS and OS) of patients with liver dysfunction and without liver dysfunction37. Figures 2 and 3 used the unadjusted data. And we performed the matching to adjust for the potential confounders using propensity score (Supplemental Fig. 1). Matching was performed with the use of a 1:1 matching protocol without replacement, with a caliper width equal to 0.05 of the standard deviation of the logit of the propensity score.

The clinical laboratory values were not normally distributed; therefore, the Mann–Whitney U test was used to analyze continuous scales. The Fisher’s exact test was used to analyze the nominal scales. For univariate screening, univariate analyses were performed. Then those risk factors deemed to have a statistically significant association with the outcome in the univariate analyses were then included in the multiple logistic regression model. We also analyzed using the forward–backward stepwise method, and the same risk factors were extracted. All recorded p values were two-sided, and differences with p < 0.05 were considered significant. All analyses were performed using JMP software, version 13 (SAS Institute Inc., Cary, NC, USA)38.

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Real-world outcomes treating patients with advanced cutaneous squamous cell carcinoma with immune checkpoint inhibitors (CPI)

https://www.nature.com/articles/s41416-020-01044-8

Abstract

Background

Immunotherapy has revolutionised the treatment of advanced cutaneous squamous cell carcinoma (cSCC). It is important to understand both safety and efficacy in a real-world and trial-ineligible cSCC population. We aimed to evaluate safety, efficacy and molecular insights among a broader cSCC population, including immunosuppressed patients, treated with immune checkpoint inhibitors (CPI).

Methods

We present a cohort of advanced cSCC patients (n = 61) treated from 2015 to 2020 evaluating the best overall response (BOR) (RECISTv1.1) to CPI therapy, immune-related adverse events (irAEs) and tumour mutational burden (TMB) to correlate with outcomes. A validated geriatric scoring index (CIRS-G) was utilised to assess comorbidities among patients ≥75. These data were compared with published clinical trial results among the broader cSCC population.

Results

BOR to CPI was lower among the entire cohort when compared with trial data (31.5 vs. 48%, P < 0.01), with higher rates of progression (59 vs. 16.5%, P < 0.01), regardless of immunosuppression history or age. Grade 3+ irAEs were more common among responders (P = 0.02), while pre-treatment lymphocyte count and TMB predicted response (P = 0.02).

Conclusions

We demonstrate comparatively lower response rates to CPI among real-world cSCC patients not explained by older age or immunosuppression history alone. Immune-related toxicity, absolute lymphocyte count and TMB predicted CPI response.
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A DNA nanodevice-based vaccine for cancer immunotherapy

https://www.nature.com/articles/s41563-020-0793-6

Abstract

A major challenge in cancer vaccine therapy is the efficient delivery of antigens and adjuvants to stimulate a controlled yet robust tumour-specific T-cell response. Here, we describe a structurally well defined DNA nanodevice vaccine generated by precisely assembling two types of molecular adjuvants and an antigen peptide within the inner cavity of a tubular DNA nanostructure that can be activated in the subcellular environment to trigger T-cell activation and cancer cytotoxicity. The integration of low pH-responsive DNA ‘locking strands’ outside the nanostructures enables the opening of the vaccine in lysosomes in antigen-presenting cells, exposing adjuvants and antigens to activate a strong immune response. The DNA nanodevice vaccine elicited a potent antigen-specific T-cell response, with subsequent tumour regression in mouse cancer models. Nanodevice vaccination generated long-term T-cell responses that potently protected the mice against tumour rechallenge.

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Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity

https://www.nature.com/articles/s12276-020-00500-y

Abstract

Cancer immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of advanced cancers. However, the tumor microenvironment (TME) functions as a formidable barrier that severely impairs the efficacy of ICIs. While the crosstalk between tumor vessels and immune cells determines the nature of anti-tumor immunity, it is skewed toward a destructive cycle in growing tumors. First, the disorganized tumor vessels hinder CD8+ T cell trafficking into the TME, disable effector functions, and even kill T cells. Moreover, VEGF, the key driver of angiogenesis, interferes with the maturation of dendritic cells, thereby suppressing T cell priming, and VEGF also induces TOX-mediated exhaustion of CD8+ T cells. Meanwhile, a variety of innate and adaptive immune cells contribute to the malformation of tumor vessels. Protumoral M2-like macrophages as well as TH2 and Treg cells secrete pro-angiogenic factors that accelerate uncontrolled angiogenesis and promote vascular immaturity. While CD8+ T and CD4+ TH1 cells suppress angiogenesis and induce vascular maturation by secreting IFN-γ, they are unable to infiltrate the TME due to malformed tumor vessels. These findings led to preclinical studies that demonstrated that simultaneous targeting of tumor vessels and immunity is a viable strategy to normalize aberrant vascular-immune crosstalk and potentiate cancer immunotherapy. Furthermore, this combination strategy has been evidently demonstrated through recent pivotal clinical trials, granted approval from FDA, and is now being used in patients with kidney, liver, lung, or uterine cancer. Overall, combining anti-angiogenic therapy and ICI is a valid therapeutic strategy that can enhance cancer immunity and will further expand the landscape of cancer treatment.

Introduction

For the last decade, immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of advanced cancers. ICIs rejuvenate dysfunctional or exhausted cytotoxic T cells (CTLs) to exert potent anti-tumor effector functions, thereby enabling effective and durable control of previously refractory cancers1,2,3. However, despite these advances, only 20–30% of patients with cancer respond to ICI treatments, and it is difficult to predict these responders before treatment because the immune system is too complex to interpret with a single biomarker. Among the various determinants of cancer immunity, the tumor microenvironment (TME) functions as a major obstacle that severely impairs the efficacy of ICIs2,4. Within the TME, the interplay between tumor vessels and protumoral immune cells generates a vicious cycle that severely disturbs anti-cancer immunity and promotes tumor progression; abnormal tumor neovessels foster protumoral immune cell evasion, which in turn bolsters tumor angiogenesis2,5,6,7. This aberrant immune-vascular crosstalk not only generates an endothelial barrier that hinders T-cell infiltration into the tumor but also impairs T-cell effector functions and even leads to T cell apoptosis within the TME2,4,8,9,10. Thus, targeting the tumor vasculature can be a potential solution to enhance anti-cancer immunity and overcome resistance to ICIs.

Here, we summarize the emerging evidence of the mutual regulation of blood vessels and immune cells within the TME and provide a rationale for a combination immunotherapy that targets both tumor vessels and immunity. In addition, we highlight the recent major clinical breakthroughs in cancer immunotherapy that have proven the validity of combining anti-angiogenic therapy and ICIs.

Tumor vasculature negatively impacts cancer immunity at multiple steps

Tumor growth depends on adequate oxygen and nutrient supply from the blood vessels11,12. However, in rapidly progressing tumors, tumor growth often exceeds the supply from the existing vasculature, resulting in intratumoral hypoxia. Hypoxia activates the angiogenic master switch, called hypoxia-inducible factor-1 (HIF-1), and upregulates vascular endothelial growth factor (VEGF) in tumors13,14,15. VEGF, in turn, promotes tumor angiogenesis by inducing the proliferation and survival of endothelial cells (ECs), forming a myriad of malformed and malfunctional neovessels within the tumor4,13,16. These tumor vessels disturb the establishment of active anti-cancer immunity at multiple steps and restrain the efficacy of ICI treatment against the tumor (Fig. 1)2,3,4,17,18.

First, an abnormal tumor vasculature serves as a physical barrier for CTLs. These tumor vessels are a chaotic network of immature microvessels without structural hierarchy, resulting in inefficient blood distribution within the tumor12,19,20. They are very leaky, have loose interconnections among the endothelium, and lack adequate wrapping by pericytes and basement membrane. Therefore, a large volume of fluid leaks from these hyperpermeable tumor vessels and accumulates in the TME, generating high interstitial fluid pressure that collapses tumor blood vessels and severely hinders blood flow into the tumor. Therefore, most tumor vessels fail to deliver enough oxygen, nutrients, and effector cells deep into the tumor. Above all, tumor-specific CTLs in the bloodstream cannot infiltrate into the TME due to this abnormal tumor vasculature and, as a result, are not able to eradicate tumor cells.

Second, the tumor vasculature disables and kills CTLs by expressing various immunosuppressive molecules, such as PD-L1 and Fas ligand (FasL, also known as CD95L). PD-L1 on the tumor endothelium can be upregulated by chronic hypoxia or interferon-γ (IFN-γ) and inactivate T cells within the tumor vascular lumen, which become functionally anergic before migrating across the vessel wall and entering the TME21. Moreover, a substantial proportion of tumor vessels overexpress FasL, a death ligand for activated T cells, on their surface. FasL on tumor vessels selectively kills CTLs but not regulatory T cells (Tregs) because of their high expression of c-FLIP, resulting in rare CTL but predominant Treg infiltration in the TME21.

VEGF, the critical driver of tumor angiogenesis, is a potent immunosuppressive factor in both innate and adaptive anti-tumor immunity. VEGF in the TME interferes with the maturation of dendritic cells (DCs) from immature precursors, thereby interrupting T-cell priming against tumors22. VEGF binding to VEGFR1 hinders the maturation of DCs through the inactivation of NF-kB signaling in murine tumor models23. Moreover, increased plasma VEGF levels correlate with an increased number of immature DC precursors but a decreased number of DCs in the peripheral blood of patients with cancer. Anti-VEGF treatment reverses this VEGF-mediated immunosuppression on DCs; it not only decreases immature progenitors but also increases mature DCs. VEGF also plays an immunosuppressive role in the TME by accumulating Tregs and repolarizing tumor-associated macrophages (TAMs) to M2-like phenotypes2,5. In addition, VEGF induces the TOX-mediated exhaustion program in CD8+ CTLs24. TOX is a recently elucidated transcription factor for T-cell development that plays an important role in T-cell priming25. In the TME, excess VEGF upregulates TOX expression in CD8+ T cells and initiates TOX-mediated transcriptional reprogramming toward the exhausted state and upregulates multiple checkpoint inhibitor receptors on these T cells24. Notably, conditional knockout of VEGFR2 in CD8+ T cells could downregulate TOX and reactivate tumor-specific CD8+ T cells, indicating the potential of VEGF/VEGFR2 axis-targeted therapy in rejuvenating exhausted T cells24.

In addition to VEGF, other pro-angiogenic factors are also involved in tumor angiogenesis and immune suppression within the TME. Angiopoietin (ANGPT) binding to the receptor tyrosine kinase Tie-2 regulates tumor angiogenesis and vascular integrity. While ANGPT1 stabilizes the tumor vasculature through recruitment of pericytes to growing vessels, ANGPT2 strongly promotes excessive angiogenic sprouting with reduced pericyte coverage. Furthermore, ANGPT2 negatively influences tumor immunity by recruiting M2-like TAMs and Tie-2-expressing monocytes/macrophages (TEMs) into tumors; TEMs then promote Treg infiltration via IL-10 but suppress CTL activation3,26. Transforming growth factor-β (TGF-β) is another important factor that regulates the proliferation of pericytes and ECs and induces different angiogenic responses depending on the balance between ALK1 and ALK5 signaling. Notably, TGF-β/ALK1 signaling activates Smad1/5, which promotes EC proliferation, migration, and tube formation. Moreover, TGF-β inactivates tumor immunosurveillance by inhibiting NK and T cells, leading to tumor progression27,28. Placental growth factor (PlGF), another member of the VEGF family, is an important regulator of the pro-angiogenic phenotype within the TME. PlGF directly interacts with VEGFR1 to stimulate tumor angiogenesis, increase vascular permeability, and promote TAM repolarization to the M2 phenotype. PlGF blockade induces vessel normalization and macrophage polarization from the M2-like to M1-like phenotype29,30.

Last, tumor blood vessels foster immune evasion by preferentially recruiting immunosuppressive immune cells into the TME. As noted above, abnormal tumor vessels give rise to a hypoxic TME. This promotes the secretion of soluble chemotactic factors, such as CCL2, CCL22, CCL28, CXCL8, and CXCL12, which facilitate the recruitment of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), M2-like TAMs, and Tregs, into the tumor2,5. These immune cells collaborate with tumor cells to suppress the magnitude of the anti-tumor immune response in the TME, thereby promoting tumor progression.

Several clinical studies also support a possible resistance mechanism against immunotherapy by VEGF. The liver is one of the most well-known hypervascular organs and has a high VEGF level compared with other organs31, and cancer patients with liver metastasis showed poorer clinical benefit from anti-PD-1 monotherapy in non-small cell lung cancer (NSCLC), melanoma, or kidney cancer32. Moreover, a recent study revealed that liver metastatic lesions have the lowest response rate compared with other organs in organ-level response analyses of patients with NSCLC treated with anti-PD1 therapy33. Intriguingly, patients with liver metastasis showed significantly less CD8+ T cell infiltration into the tumor compared with those without liver metastasis32, suggesting VEGF-mediated T cell exclusion within tumors and explaining the attenuated response to anti-PD-1 therapy in VEGF-high tumors. Such results warrant further investigation of the immunoregulatory effects of VEGF blockade on VEGF-high tumor lesions such as liver metastases.

Targeting the tumor vasculature: from vascular destruction to vascular normalization

The original concept of anti-angiogenic therapy simply focused on inhibition of new vessel formation and the destruction of established vessels to starve tumor cells to death. However, this concept leads to a therapeutic paradox in which excessive anti-angiogenic therapy could cut not only the intratumoral blood supply but also the delivery of concurrent anti-cancer drugs and anti-cancer immune cells, such as CTLs into the tumor. Moreover, additional concerns were raised from preclinical studies suggesting that complete blockade of intratumoral blood flow could result in extreme hypoxia within the TME, which could accelerate local invasion and distant metastases of tumor cells and even induce severe immunosuppression within the TME34. To resolve this paradox, Jain et al. proposed a vascular normalization theory in which a judicious intensity of anti-angiogenic therapy could result in an equilibrium between anti-angiogenic and pro-angiogenic signals within the TME—vascular normalization status—and enable efficient delivery of oxygen, drugs, and anti-cancer immune cells into the tumor, rather than inducing excessive destruction of vessels and intratumoral hypoxia35,36. In other words, stronger therapy may not always be better; lower, optimal-dose anti-angiogenic treatment could be more advantageous than higher-dose therapy to establish a favorable TME leading to the therapeutic benefit.

Consistently, Huang et al. reported that adequate intensity anti-angiogenic therapy is critical to alleviate intratumoral hypoxia and establish an immunosupportive TME37. In their study, high-dose anti-VEGFR2 treatment aggravated intratumoral hypoxia and restrained the infiltration of CD8+ T cells into the TME, thereby suppressing anti-cancer immunity. On the other hand, low-dose anti-VEGFR2 treatment normalized tumor vessels with increased pericyte coverage, improved tumor perfusion, and eventually promoted the infiltration of CD8+ and CD4+ T cells into the tumor. Furthermore, Jung et al. also revealed that higher-dose anti-VEGFR2 therapy could result in intratumoral immunosuppression mediated by Ly6Clow monocytes and Ly6G+ neutrophils while impairing the adaptive immune cells within the TME38,39. In line with these results, Rivera et al. also reported that higher-dose anti-angiogenic therapy could activate PI3K signaling in myeloid cells that promotes immune suppression and neovascularization40.

While evidence supporting the vascular normalization theory has been accumulating over the past decade, questions still remain. First, it is not clear whether this hypothesis could be universally applied using all anti-angiogenic agents to all stages of carcinogenesis. Next, the therapeutic dose of anti-angiogenic therapy in clinical practice varies depending on the type of tumor and its clinical setting. For example, a lower dose (5 mg/kg) of bevacizumab (anti-VEGF-A) is used in colorectal cancer, while a higher dose (15 mg/kg) is used in lung cancer. However, it is not clear which dose corresponds to either the vascular normalizing dose or vascular destructing dose in patients with cancer. Therefore, further preclinical and clinical studies are warranted to optimize anti-angiogenic therapy in the era of cancer immunotherapy to open the vascular normalization window within the TME and enhance anti-tumor immunity.

Immune cells play versatile roles in the regulation of tumor angiogenesis

Immune cells orchestrate the whole process of tumor angiogenesis via both direct and indirect mechanisms (Fig. 2). Numerous pro- or anti-angiogenic factors derived from immune cells directly influence tumor vessels and determine the endothelial phenotype and function5,7,41,42. Moreover, certain types of immune cells can communicate and polarize other types of immune cells to be either pro-angiogenic or anti-angiogenic, indirectly affecting the quantity and quality of tumor angiogenesis41,43.

Macrophages exhibit notable plasticity in the regulation of tumor angiogenesis. They constitute functionally heterogeneous innate immune cells depending on the type of secreted cytokines and growth factors. Notably, they modify their transcriptional program in response to stimuli from the TME along a continuous spectrum, with an M1- and M2-like phenotype at both extremes; M1-like TAMs suppress tumor angiogenesis, whereas M2-like TAMs promote tumor angiogenesis41,42,44,45,46.

M1-like TAMs suppress sprouting angiogenesis and induce vessel maturation by secreting anti-angiogenic cytokines, such as interleukin (IL)-12 and TNF-α47,48. Intriguingly, M1-like TAM-derived IL-12 polarizes macrophages toward the M1 phenotype, thereby generating a positive feedback loop for the anti-angiogenic M1 phenotype. Accordingly, immunotherapy with IL-12 not only reduces microvessel density but also enhances M1 macrophage polarization in tumors48,49,50.

M2-like TAMs promote tumor angiogenesis by producing pro-angiogenic growth factors (VEGF, EGF, FGF family, and PDGF-b), angiogenic CXC chemokines (CXCL8/IL-8 and CXCL12, also known as SDF-1), and angiogenesis-associated factors (TGF-b, TNF-α, and thymidine phosphorylase)51,52. These factors not only enhance the migration and proliferation of ECs but also further skew macrophage polarization away from M1 to the tumor-promoting M2 phenotype44,47,48. As M2-like TAMs are a more dominant population than M1-like TAMs in most advanced tumors, pharmacological depletion of macrophages with clodronate- liposome generally suppresses tumor angiogenesis and tumor growth in transplanted tumor models53,54.

Another distinct subtype of macrophages that was defined relatively recently is TEMs, which also plays an important role in encouraging tumor angiogenesis55,56,57. When Tie-2 on the surface of TEMs binds to angiopoietin-2 secreted from endothelial and tumor cells, a strong angiogenic switch is turned on in the TME. Consistently, tumors fail to sustain angiogenesis in the absence of Tie-2 signaling in macrophages58. In addition, selective depletion of Tie-2 expression in macrophages induces tumor vascular normalization and the regression of established tumors, supporting the critical role of TEMs during tumor angiogenesis56,57.

DCs, another important innate immune component of the TME, can regulate tumor angiogenesis depending on their maturation status59. Mature DCs can be classified into two major subtypes, conventional DCs (cDCs) or plasmacytoid DCs (pDCs)60,61. Mature cDCs suppress tumor angiogenesis by secreting anti-angiogenic cytokines, namely, IL-12 and IL-18, and angiostatic chemokines, including CXCL9, CXCL10, and CCL2162,63,64. In contrast, mature pDCs secrete interferon-α (IFN-α), which inhibits the proliferation and motility of ECs and increases anti-angiogenic cytokines and chemokines in the tumor65,66. Unfortunately, in the TME, the most frequent subset of DCs is immature DCs (iDCs) because cancer cells can preferentially recruit iDCs from peripheral blood vessels by releasing a number of cytokines (e.g., VEGF, β-defensin, CXCL12, HGF, and CXCL8)64,67,68,69.

MDSCs, a heterogeneous population of immature myeloid cells, can augment tumor angiogenesis via several mechanisms. MDSCs enhance angiogenesis by increasing IL-10 and decreasing IL-12 in the TME43,45,46,70. Furthermore, MDSCs can promote angiogenesis by producing Bv8 and MMP-9. MDSC-derived Bv8 can directly promote neovessel formation via endocrine gland-derived VEGF1 (EG-VEGF1) and VEGF2 (EG-VEGF2) and can further accumulate MDSCs within the tumor71,72,73. Therefore, neutralizing antibodies against Bv8 significantly reduce tumor vascular density and the number of tumor-infiltrating MDSCs72. Simultaneously, MMP-9 can induce tumor angiogenesis by releasing biologically active VEGF from the extracellular matrix of the TME. Accordingly, MMP-9-deficient MDSCs fail to induce tumor angiogenesis46,73. Third, unlike other immune cells, some MDSCs can differentiate into EC-like cells. These EC-like MDSCs express endothelial markers, such as CD31 and VEGFR2, and have the ability to integrate into the tumor vasculature45,46,73.

Adaptive immune cells are also critical players in the orchestration of tumor angiogenesis by directly affecting EC biology and indirectly modulating myeloid cell phenotypes. Among adaptive immune cells, CD8+ CTLs play a critical role in suppressing tumor angiogenesis by secreting IFN-γ74,75. IFN-γ directly inhibits the proliferation and migration of human endothelial cells and secretes IFN-inducible protein 10 (IP-10) and monokine induced by IFN-γ (MIG). These cytokines also react with CXCR3, restraining the proliferation of endothelial cells and tumor vascularization74,76. Furthermore, IFN-γ signaling downregulates VEGF-A but upregulates CXCL9, CXCL10, and CXCL11, which collectively stimulate vascular maturation by enhancing pericyte recruitment along ECs74,77,78. Another important aspect of IFN-γ in tumor angiogenesis is the reprogramming of TAMs from M2- to M1-like TAMs. Hyperactive IFN-γ/STAT1 signaling promotes M1-like TAM reprogramming, leading to vascular remodeling and consequent tumor eradication7,77,79.

In addition to CD8+ CTLs, CD4+ T helper 1 (TH1) cells assist in tumor vessel normalization by producing IFN-γ in the TME. Depletion of CD4+ TH1 cells decreases pericyte coverage and increases malformed tumor vessels in multiple mouse tumor models, whereas activation of CD4+ T cells improves vessel normalization7,80,81. TH1 cells also polarize M2-like TAMs to M1-like TAMs and induce DC maturation in the TME, which suppresses tumor angiogenesis82,83.

In contrast to CD8+ CTLs and TH1 cells, TH2 cells promote robust tumor angiogenesis. TH2 cells expressing IL-4, IL-5, and IL-13 recruit M2-like TAMs through STAT-6 activation and promote tumor angiogenesis41,50,77,84. TH17 cells, another subtype of CD4+ T cells, are associated with increased angiogenesis in various human cancers. The expression of IL-17 by TH17 correlates with the infiltration of ECs and abnormal tumor vasculature41,77,85,86.

Tumor-infiltrating Treg cells also play a critical role by sustaining angiogenesis directly through VEGF secretion and supporting endothelial cell recruitment and expansion83,87. Furthermore, Tregs promote angiogenesis indirectly by restraining the activity of TH1 cells and by triggering the activation of M2-like macrophages42. In ovarian cancer, hypoxia results in CCL28 upregulation, leading to a robust increase in Treg infiltration, VEGF and blood vessels, whereas depletion of Tregs reduces intratumoral VEGF levels and tumor angiogenesis18,81.

Preclinical studies provide a rationale for combining anti-angiogenesis therapy with ICIs

The interactions between tumor immunity and angiogenesis suggest that tumor vascular remodeling could enhance the efficacy of cancer immunotherapy. Emerging preclinical evidence demonstrates the potential of combining immunotherapy with vascular-targeting treatment24,37,75,88,89,90,91. Allen et al. demonstrated that anti-angiogenic therapy with anti-VEGFR2 enhances the efficacy of anti-PD-L1 immunotherapy in pancreatic neuroendocrine tumor (RT2-PNET), mammary carcinoma (MMTV-PyMT), and glioblastoma (NFpp10-GBM) models88. Anti-VEGFR2 treatment upregulated the expression of PD-L1 via IFN-γ secretion by CD8+ T cells to potentially enhance the sensitivity of anti-PD-L1 therapy in tumors. Furthermore, the combination of anti-angiogenic and immunotherapy increased pericyte coverage and normalized tumor vessels, promoting intratumoral infiltration of activated T cells. In addition to vascular normalization, the vessel phenotype represents the characteristics of high endothelial venules (HEVs), which are morphologically thickened with plump endothelial cells (ECs) and functionally more specialized in lymphocyte extravasation than other tumor ECs. Notably, the LTβR signaling pathway is involved in the generation of intratumoral HEVs after combined treatment with anti-VEGFR2 and anti-PD-L1. Therefore, these results suggest that anti-angiogenic therapy could improve the efficacy of cancer immunotherapy and overcome resistance to cancer immunotherapy via tumor vessel normalization and intratumoral HEV formation. Shigeta et al. also reported consistent synergism of anti-VEGFR2 and anti-PD-L1 in hepatocellular carcinoma (HCC)89. They observed that anti-VEGFR2 therapy upregulates PD-L1 expression under hypoxic conditions, mediated in part by IFN-γ secreted by ECs. Combination therapy with anti-VEGFR2 and anti-PD-1 also promoted durable vascular normalization, which is mediated by PD-1-expressing CD4+ cells. Dual combination therapy has also been shown to improve overall survival (OS) and anti-cancer immunity with increased intratumoral accumulation of CTLs and M1-like TAMs. Collectively, combination therapy with anti-VEGFR2 and anti-PD-1 reprograms the immune microenvironment via vessel normalization, further strengthening the anti-cancer immune response and overcoming resistance to cancer immunotherapy in HCC.

Anti-angiogenic therapy can also overcome resistance to anti-PD-1 by abolishing the TOX-mediated T-cell exhaustion program in the TME24. Kim et al. revealed that VEGF significantly upregulates the transcription factor TOX, which influences the phenotype and function of CTLs. The TOX-mediated transcriptional program resulted in severe T-cell exhaustion and upregulated inhibitory immune checkpoint receptors such as PD-1, TIM-3, LAG-3, and TIGIT and reduced the proliferation of cytokine production by CTLs. Combination treatment with anti-VEGFR2 and anti-PD-1 enhanced the immunotherapeutic efficacy and T-cell reinvigoration. Collectively, combinatory treatment with anti-angiogenic agents and ICIs is a potential therapeutic option in anti-PD-1-resistant cancer.

Modulating another important angiogenic pathway, ANGPT2/Tie2, has also demonstrated promising preclinical efficacy when combined with anti-VEGF and anti-PD-1. Schmittnaegel et al. demonstrated that combined blockade of VEGF-A and ANGPT2 by a bispecific antibody (A2V) enhanced the therapeutic activity compared with either anti-VEGF-A or anti-ANGPT2 monotherapy alone in both genetically engineered and transplant tumor models90. A2V effectively inhibited tumor angiogenesis but promoted vascular maturation in the TME. Moreover, A2V increased tumor antigen presentation by DCs and activated tumor antigen-specific CD8+ CTLs, remodeling intratumoral immunity. Although A2V enhanced perivascular CD8+ CTL accumulation, it also upregulated PD-L1 expression on tumor vessels via IFN-γ-mediated negative feedback. This negative feedback mechanism was successfully overcome by combining A2V with anti-PD-1, leading to better immunotherapeutic efficacy. These results encourage further testing of combining ICIs with various anti-angiogenic targets other than VEGF in advanced cancers.

Recently, a novel immunotherapeutic target, simulator of IFN genes (STING), was reported to be involved in the regulation of the tumor vasculature and demonstrated synergism with anti-VEGFR2 and ICIs75. Yang et al. revealed that intratumoral STING signaling activation suppresses tumor angiogenesis and induces vessel normalization through type I IFN signaling activation and the upregulation of genes related to vascular normalization and endothelial-lymphocyte interaction. Intriguingly, CD8+ CTLs are involved in STING-induced vascular remodeling. STING agonist combined with anti-VEGFR2 synergistically enhanced vascular normalization, leading to durable anti-cancer immunity. Notably, STING-based immunotherapy was most effective when combined with anti-VEGFR2 and/or ICIs (either anti-PD-1 or anti-CTLA-4), leading to the complete regression of tumors that are resistant to either anti-angiogenic monotherapy or ICI monotherapy. Therefore, these data suggest that combining novel therapeutics with the combination of anti-angiogenic agents and ICIs could help overcome resistance to anti-angiogenic and immunotherapy in refractory cancers.

On the other hand, immune checkpoint blockade, such as anti-CTLA-4 or anti-PD-1, increases vascular perfusion to improve therapeutic efficacy. Zheng et al. demonstrated that ICI therapy elicits IFN-γ production in CD8+ T cells, leading to increased vessel perfusion (IVP)91. Notably, IVP can distinguish tumors that are sensitive to ICIs from those that are resistant. In addition, IVP was time-dependently induced by anti-CTLA-4 even before tumor regression was detectable. Collectively, these findings indicate that IVP could be a prerequisite of ICI to improve anti-cancer immunity, thereby enabling it to be used as a predictive indicator for ICI efficacy.

Clinical evidence for combining anti-angiogenic agents and ICIs in cancer treatment

Preclinical studies continue to yield encouraging results regarding the synergistic effects of ICIs and anti-angiogenic agent combination therapy, which have led to clinical investigations to reproduce these results in patients with advanced cancer92,93,94,95,96,97,98. Several pivotal clinical trials have already demonstrated the superiority of combining anti-angiogenic agents and ICIs in various malignancies. The most successful results of combination therapy have been reported in renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).

RCC is a highly immunogenic tumor that has been treated with high-dose IL-2 in some patients. However, its clinical benefit is limited due to the strong toxicity and the limited number of patients who benefit from it, although approximately 10% of patients do achieve a durable response. Immunotherapy has recently been revisited and reevaluated when phase 3 clinical trials demonstrated that nivolumab (anti-PD-1) treatment leads to longer OS with significantly lower toxicity. Research is currently being conducted to maximize the efficacy of immunotherapy by combining PD-1/PD-L1 inhibitors with VEGFR inhibitors. In KEYNOTE-426, patients with previously untreated metastatic RCC were treated with either pembrolizumab (anti-PD-1) and axitinib (VEGFR1, 2, and 3 inhibitor) combination therapy or sunitinib monotherapy, and significantly increased progression-free survival (PFS) was demonstrated in the combination group compared with the sunitinib group93. The combination group had a 47% reduced risk of death, and the objective response rate (ORR) of the combination group was 59.3% compared with 35.7% in the sunitinib group. Although the incidence of hepatic toxicity was higher in the combination group, no relevant death event occurred. Based on the significant efficacy and acceptable toxicity profile, combination therapy with pembrolizumab and axitinib was approved by the FDA for treatment-naïve patients with metastatic RCC. JAVELIN Renal 101 (NCT02684006) is a phase 3 clinical trial that evaluated the efficacy of avelumab (anti-PD-L1) and axitinib combination therapy against sunitinib monotherapy in patients with metastatic RCC in a first-line setting94. Although the data are premature for OS analysis and require further follow-up, the median PFS of the combination group has already been reported to be 13.8 months compared with 8.4 months for sunitinib. In addition, the ORR and complete response rate were 51.4% vs. 25.7% and 3.4% vs. 1.8%, respectively, showing that these indices have almost doubled. Grade ≥3 toxicity was comparable (71.2% vs. 71.5%) between the two groups. Based on this study, the FDA approved avelumab for use in combination with axitinib as first-line treatment for patients with advanced RCC. Additional clinical trials are ongoing in patients with advanced RCC based on preexisting studies that showed promising results with PD-1/PD-L1 inhibitor and anti-angiogenic agent combination therapy.

In HCC, two highly anticipated phase III studies testing PD-1 inhibitor monotherapy failed to meet their primary endpoints, leading to doubts regarding the use of ICIs in this cancer. However, a randomized phase III clinical trial, IMBRAVE 150 (NCT03434379), demonstrated significant improvements in co-primary end points, PFS and OS, using the combination of atezolizumab (anti-PD-L1) and bevacizumab (anti-VEGF-A) compared with sorafenib95. This was the first study to propose a new first-line treatment option that is superior to sorafenib, which has been the standard of care for a decade. This study was initiated from a phase Ib study exploring the efficacy of combining atezolizumab and bevacizumab in patients with various gastrointestinal cancers, including HCC, gastric cancer, pancreatic cancer, and esophageal cancer (GO30140/NCT02715531). At the 2018 ASCO annual meeting, the researchers of this phase Ib study presented that the early-stage ORR was >60% in advanced HCC (investigator-assessed response, 61%; independent review facility-assessed response, 65%)96. The FDA granted the Breakthrough Therapy designation based on these data, and the phase III IMBRAVE 150 trial was initiated. At the ESMO Asia 2019 Congress, the median OS with the atezolizumab and bevacizumab combination was not reached until analysis when compared with 13.2 months with sorafenib (p = 0.0006); the median PFS was 6.8 months versus 4.5 months (p < 0.0001), and the ORR was 27% versus 12% (p < 0.0001), respectively95. In particular, the ORR of this combination was a huge improvement given that the ORRs for anti-PD-1 inhibitor monotherapy were only 15–20% in patients with advanced HCC. In addition, grade 3–4 adverse events (AEs) were reported in 57% of patients in the combination group compared with 55% of patients in the sorafenib group. In terms of patient-reported outcomes, the combination group exhibited delayed deterioration of quality of life compared with sorafenib. The safety and efficacy of the combination of pembrolizumab and lenvatinib were evaluated in patients with unresectable HCC in KEYNOTE-524, a multicenter, open-label, single-arm phase Ib study97. This clinical trial also yielded a promising response rate during the early stage and was granted Breakthrough Therapy designation by the FDA, initiating LEPP-002, a phase 3 trial to evaluate pembrolizumab in combination with lenvatinib as a potential first-line treatment for patients with advanced HCC97.

In non-squamous non-small cell lung cancer (NSCLC), a phase 3 clinical trial (Impower150, NCT02366143) comparing atezolizumab (anti-PD-L1), bevacizumab (anti-VEGF), carboplatin, and paclitaxel combination therapy (ABCP group) against bevacizumab, carboplatin, and paclitaxel combination therapy (BCP group) showed significantly extended PFS and OS in the ABCP group compared with the BCP group (median PFS: 8.3 vs. 6.8 months; median OS: 19.2 vs. 14.7 months)92. The ORR was significantly higher in the ABCP group than in the BCP group (ORR: 63.5% vs. 48.0%), whereas the adverse event rate was comparable. Based on these results, atezolizumab was approved by the FDA for use in combination with bevacizumab, paclitaxel, and carboplatin as first-line treatment for patients with metastatic non-squamous NSCLC.

Recently, the FDA granted accelerated approval for the use of a combination of pembrolizumab and lenvatinib in patients with advanced endometrial cancer who have experienced disease progression after systemic therapy. This approval was based on the results of the single-arm, multicenter, open-label, multicohort phase Ib/II KEYNOTE-146 trial (NCT02501096)98. In this trial, 108 patients who had previously been treated for metastatic endometrial cancer were evaluated for their response to lenvatinib and pembrolizumab. Interim analysis showed that the ORR was 39.6% and 45.3% at 24 weeks by investigator review and independent review, respectively. The most common treatment-related adverse events (TRAEs) of any grade to be reported were hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%). Of the grade 3 TRAEs, the most common were hypertension (34%) and diarrhea (8%), whereas no cases of grade 4 TRAEs were reported. However, immune-mediated AEs, including endocrine, gastrointestinal, hepatic, skin, pulmonary, and renal events, occurred in 55.6% of patients, and 10% of the patients required high-dose glucocorticoids.

In addition to the abovementioned clinical trials, numerous studies are ongoing in various malignancies to prove the efficacy of combining PD-1/PD-L1 inhibitors and anti-VEGF agents (Table 1, https://clinicaltrials.gov). In several years, these ongoing trials are expected to generate consistent results, which will evolve the therapeutic landscape of advanced cancers.

Conclusion

Years of research have demonstrated the potential of ICI monotherapy as well as its limitations, which have led to further attempts to overcome these limitations by combination immunotherapy. Of the potential candidates, the combination of ICI and anti-angiogenic agents continues to yield promising results in both preclinical and clinical studies, not only highlighting that it is one of the most effective combination immunotherapy regimens thus far but also changing the treatment landscape for RCC and HCC. Nonetheless, several issues remain to optimize the efficacy of this combination therapy. First, predictive biomarkers must be developed to identify the subset of patients who will benefit from this combination treatment. Second, the focus on anti-VEGF/R agents as the main anti-angiogenesis agent should be diversified to agents targeting other candidates, such as FGF/R, PDGF/R, and ANGPT2, among others. Third, whether the effects of this combination are synergistic or merely additive must be evaluated. Finally, the angiogenic phenotype differs according to organ; thus, more in-depth analyses must be performed to further our knowledge of the response to ICI treatment at the organ level.
curncman
Posts: 496
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The microbiome and its effects on the immune system

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The microbiome and its effects on the immune system

curncman
Posts: 496
Joined: Fri Jun 26, 2020 8:27 am

Re: What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

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Parker Institute for cancer immunotherapy San Francisco, is probably good place to sell Nano Stilbene, nanoPSA to cancer patients
curncman
Posts: 496
Joined: Fri Jun 26, 2020 8:27 am

Gene expression profile of human T cells following a single stimulation of peripheral blood mononuclear cells with anti-

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Gene expression profile of human T cells following a single stimulation of peripheral blood mononuclear cells with anti-CD3 antibodies

https://bmcgenomics.biomedcentral.com/a ... 019-5967-8

CD8+CD57+ T cells exhibit distinct features in human non-small cell lung cancer

https://jitc.bmj.com/content/8/1/e000639

Sylvester Comprehensive Cancer Center: Committed to Cancer Research and Care During Covid 19



Dendritic cells generated in the presence of
interferon-a stimulate allogeneic CD4+ T-cell
proliferation: modulation by autocrine IL-10,
enhanced T-cell apoptosis and T regulatory
type 1 cells

https://watermark.silverchair.com/dxh10 ... yX4rChIdGc
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