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

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

Future challenges in immunotherapy

Post by curncman »

https://www.nature.com/articles/s41423-020-00530-6

Cellular immunotherapy
Natural killer (NK) and lymphokine-activated killer (LAK) cells
Natural killer (NK) cells were described in the 1970s based on their capacity to eliminate tumor cells without prior sensitization, with differences observed compared with specific cytotoxic T cells (which are activated based on the recognition of the target cells)262,263. In 1985, Piontek et al. reported that NK cells have the ability to preferentially kill cells that had lost the expression of the major histocompatibility complex class I molecules264,265.

Lymphokine-activated killer (LAK) cells are a heterogeneous population that includes not only NK but also NKT and T cells, which can be generated in an in vitro culture of peripheral blood mononuclear cells (PBMCs) in the presence of IL-2266. Dr. Rosenberg and collaborators carried out studies using these cells in the presence of IL-2 (reviewed by Rosemberg251). These LAK cells showed good antitumoral responses in 22% of the melanoma patients who received them as therapy250. However, secondary effects such as liver toxicity and the expansion of the Treg population limited their therapeutic effect. Researchers started to design new recombinant IL-2 with some mutations to avoid the activation of Tregs267, with linking it to polyethylene glycol (PEG) to increase its half-life and efficacy268.

Another cytokine described later, IL-15, showed similarities to IL-2 in many respects269, and it had some unique advantages, such as the capacity to activate NK and cytotoxic T cells (Tc) but not Tregs. IL-15 is being used in different versions (alone, as a heterodimer with receptor IL-15/IL15Ra or IL15Rα IgFc, or in an agonist complex with ALT-803)269 and in combination with other therapies in several clinical trials (examples: NCT01021059, NCT03905135, and NCT03759184).

More recently, researchers have focused their attention on other cytokines and combinations (such as IL-15, IL-12, and IL-18)270, which are able to activate NK cells in vitro and induce a good responses in animal models. In some human clinical trials, remission has been observed for patients with acute myeloid leukemia271,272, which broadens the options for the use of NK cells in the treatment of this pathology.

The properties of NK cells reveal their versatility as treatments against tumors. NK cells are able to kill tumors through several mechanisms, including receptor-mediated cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and death receptor-mediated apoptosis, but they also secrete cytokines such as interferon gamma that enhance the antitumoral adaptive immune response. NK cell adoptive transfer (either autologous or allogenic NKs) is currently being tested in clinical trials for hematological diseases and solid tumors, and numerous research groups have recognized their potential in other situations, such as transplant rejection and pregnancy. NK cell lines, memory-like NK cells and stem cell-derived NK cells are additional types of cells that can be used for tumor immunotherapy273.

Regarding other cellular therapies, NK cells as substitutes for T cells for use upon transformation with an chimeric antibody receptor (CAR) are being explored (see below).

Dendritic cells
Paul Langerhans identified dendritic cells in human skin in 1868274, but these cells were not named until 1973 by Dr. Ralph M. Steinman (Nobel Prize in 2011) and Dr. Zanvil A. Cohn, who chose the term because the cell morphology, with long extensions, resembles that of neuronal dendrites275. In humans, dendritic cells are obtained from different sources that vary in origin, maturation state and tissue distribution (skin, lymphoid tissue, circulating cells). Among the main types of dendritic cells, plasmocytoids are conventional myeloid DC1 and DC2, pre-DC and monocyte-derived dendritic cells. In the epidermis, there are three types: Langerhans cells (LC), monocyte-derived LC-like cells and inflammatory dendritic epidermal cells (IDECS)276. As indicated above, DCs are antigen-presenting cells and are the only cells that are able to activate naïve T lymphocytes. A subpopulation of DCs also carries out a process known as cross-presentation. In this way, they facilitate the activation of both helper and cytotoxic T lymphocytes277. In addition to their participation in the immune response, they can be used in antitumoral therapeutic vaccines277,278.

It is possible to generate a type of blood monocyte-derived dendritic cell in the presence of a mixture of cytokines in culture279—a process that induces their subsequent maturation and activation in the presence of tumor antigens (cell lysates, recombinant or purified antigens, peptides, RNA, DNA, and viral vectors280). These cells can also be obtained from bone marrow hematopoietic CD34 + progenitor cells281. Other sources, such as circulating or skin dendritic cells, are relatively scarce and are therefore not usually used.

After their differentiation and activation in vitro278,282, DCs are exposed to tumor antigens and infused back into the patient (either by blood infusion or injected into areas near the lymph nodes or even directly into them) to reach the secondary lymphoid organs as soon as possible, at which point they can present antigens to the T cells. This approach is a type of individualized therapy and is therefore expensive.

The first approved vaccine in which autologous dendritic cells were used was Sipuleucel-T (Provenge)283, which was a treatment for prostate cancer refractory to hormonal treatment. Immunotherapy with dendritic cells is currently being tested in more than 200 clinical trials for various tumors: brain, pancreas, mesothelioma, melanoma and many others (ClinicalTrials.gov Identifiers: NCT01204684, NCT02548169, NCT02649829, and NCT03300843, respectively). The data indicate that the therapy is well tolerated and has led to increased patient survival in some trials. Furthermore, complete cure and partial remission outcomes have also been observed. The lack of efficacy on other tests was probably due to the presence of immunosuppressive factors in the tumor environment.

Another therapeutic use of dendritic cells involves their induction of immunosuppression both in transplants and in autoimmune diseases284. In an autoimmune pathology such as multiple sclerosis, the intention is to achieve stable tolerogenic dendritic cells that can act against some autoantigens (such as myelin peptides) in the presence of vitamin D3, dexamethasone, or other agents285. Phase I clinical trials have generally shown good tolerance to this therapy without serious adverse effects286.

However, greater control of this treatment is necessary in several respects to obtain the best therapeutic results284; e.g., the type of dendritic cells and ex vivo differentiation, the antigens used, and the injection route are important considerations.

Gamma/delta T cells (Tγ/δ)
Human T cells expressing γ/δ TCR cells have interesting properties, including the capacity to kill a broad range of tumor cells. The advantages of these cells in cancer therapy are based on their independence from MHC expression on tumor cells and that their relative insensitivity to some inhibitor molecules (such as PD-1). The initial clinical application, with the adoptive transfer of autologous Vδ2+ cells after ex vivo expansion, showed only sporadic responses287, and different exploratory studies are currently being carried out to increase their clinical therapeutic use. Allogeneic Vδ2+ cells are also being explored in cancer therapy; e.g., they are being used against refractory hematological malignancies288 and advanced cholangiocarcinoma289.

Regulatory T cells (Tregs)
Although the basis of immune regulation was suggested centuries ago, regulatory T cells were described by Sakaguchi et al. as CD4+ CD25+ natural regulatory T cells290 that expressed the forkhead box P3 transcription factor (foxp3)291. Later, induced or adaptive regulatory T cells were also identified, including different subsets that carry several phenotypic markers and express various cytokine secretion profiles292. All of these factors play crucial roles in the maintenance of immunological self-tolerance by suppressing autoreactive T cells.

The manipulation of Tregs to achieve therapeutic outcomes is a field of great interest, because of both their expansion and activation in diseases, such as allergic and autoimmune diseases, and as a potential targets for cancer immunotherapy293.

Tumor-infiltrating lymphocytes (TILs)
Lymphocytes that infiltrate solid tumors are called tumor-infiltrating lymphocytes (TILs). In 1957, Thomas and Burnet proposed that the immune system performs tumor immune vigilance, with lymphocytes as sentinel cells leading to the elimination of somatic cells transformed by spontaneous mutations294,295.

Since the end of the 1980s, Dr. Rosenberg has been trying to prove and improve the effective use of TILs. The process starts with surgery and the isolation of TILs from a tumor, followed by TIL activation in culture in the presence of cytokines, cellular expansion and, finally reinfusion into the patient. Since its inception, this therapy has been improved markedly, with an increase in optimal responses from less than 30% to the current 50–75%, in some cases. These higher success rates are due, in particular, to the prior preparation of the patient, including the depletion of lymphoid tissues, to avoid an expansion of regulatory cells296, myeloid suppressor cells and other cells that can compete with the transferred TILs.

Currently, there are more than 200 trials in which TILs are being used alone or in combination with other immunotherapies on several tumors, such as melanoma, metastatic colorectal cancer, glioblastoma, pancreatic cancer, hepatobiliary cancer, ovarian cancer and breast cancer. This individualized therapy has limitations; it can only be used on solid tumors, and the number and specificity of the TILs and the type of tumor and microenvironment make standardizing this therapy difficult.

Chimeric antigen receptor (CAR)
Since TILs include a variety of T lymphocytes with different specificities, the next step was to obtain T cells of a single type (monoclonal cells) carrying a clonal receptor capable of recognizing tumor antigens. This effort was carried out for the first time in mice and subsequently, in 2006, in humans with a transgenic TCR against the MART-1 melanoma antigen297,298. These types of receptors are known as tTCRs, but their ability to recognize antigens is restricted since they can only identify the peptides presented by antigen-presenting cells on self-histocompatibility molecules.

This situation changed because of one of the latest revolutions in antitumor therapy, the development of T lymphocytes that carry a chimeric antigen receptor (CAR) based on a specific antibody directed to a target surface molecule299,300. These modified T cells can directly recognize tumor cells without required antigen processing or presentation by professional antigen-presenting cells. Moreover, the CAR includes all of the necessary elements for intracellular signaling and activation of helper and cytotoxic T lymphocytes.

CAR therapy was developed by one of its pioneers, Dr. Carl June at the University of Pennsylvania in the United States300, who used modified T lymphocytes that carried a chimeric antigen receptor to target CD19+ leukemic B cells. After interacting with CD19+ cells, these modified CAR T cells were activated and able to proliferate and exert cytotoxic functions against target cells. In this case, both tumor and healthy B cells were affected. Although bone marrow continues to produce B lymphocytes, in cases of severe B lymphopenia, it is possible to provide exogenous immunoglobulins periodically.

The whole process of the current CAR T-cell therapy begins with blood donation, from which lymphocytes are purified and genetically modified in vitro by a viral vector, which carries the genes coding for the chimeric antigen receptor. The cells are expanded in the presence of cytokines in culture and are subsequently reinfused into the patient. This type of cellular immunotherapy is individualized for each patient, with his/her CAR T cells ultimately destroying the tumor.

Since the first generation of CARs appeared, namely, a chimeric receptor composed of an anti-CD19-specific single-chain variable fragment linked to a transmembrane domain and intracellular signaling domain of the T cell receptor (CD3 ζ chain), researchers started to modify the original design. New generations of CARs, including the CD3 ζ subunit together with other signaling domains, such as CD28, CD134, CD137 (4–1BB), CD27, and ICOS, or combinations (CD3 ζ, CD28, and CD134)301, have been developed in the second and third generations of CARs to improve several aspects, such as the activation, proliferation and survival of CAR T cells. The fourth generation of CARs show improved the antitumoral effects by carrying additional molecules (such as cytokines or drugs), improvements to the safety of CAR T-cell therapy through the use of suicide genes301 and many new designs, such as dual CARs or the so-called split universal and programmable (SUPRA) CAR system302.

In addition to T cells, other types of cells, such as NK cells, are now being explored for use in antitumoral responses303. In an effort to avoid using personalized treatment, researchers are now working on universal CARs that may be used on many different patients without inducing the problem of rejection304,305,306,307.

The encouraging results obtained with this therapy have led to interest from companies, and some commercialized examples are available, although many more “in-house” or academia-produced CARs are in clinical trials. CAR T-cell therapy was initially designed for use against hematological cancers (leukemia and lymphomas), but many new opportunities have been opened for its use against solid tumors308, infectious diseases (such as HIV)309, allotransplantation, autoimmune diseases310 and severe allergies311. China and the USA are the leading countries in producing CAR T-cell therapy, and numerous clinical trials are underway.

Immunotherapy for COVID-19 patients
Coronavirus disease 2019 (COVID-19), which is produced by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), affects millions of people in many countries. Most of the infected patients (80–85%) are asymptomatic or have mild symptoms, but the disease in some patients progresses to a moderate or severe illness that requires hospitalization in intensive care units because of respiratory distress, multiorgan failure, and/or other pathologies, and more than one-half million fatal cases have been reported worldwide. The most vulnerable population includes aging patients and those with comorbidities such as hypertension, diabetes and cardiovascular diseases.

There are several aspects of the COVID-19 pathogeny that suggest an overreaction of the immune system in severely ill patients, with increased levels of inflammatory cytokines such as IL-6, IL-1 and others (creating the so-called “cytokine storm”), together with blood lymphopenia and CD8 T cell and NK cell exhaustion. Special therapies have not yet been identified to cure these patients, and preventive vaccines are not yet available, but some immunotherapies have been proposed as adjunct therapies, and some of these are currently in different phases of clinical trials312.

The immunotherapeutic strategies include the following:

1.
Targeting inflammatory molecules. To attenuate the cytokine storm (IL-6 receptor, IL-6, IL-1, GM-CSF, VEGF, etc.), monoclonal antibodies against receptors and/or cytokines, receptor antagonists and/or inhibitors are proposed.

2.
Passive immunotherapy. Patients who were infected and recovered, but developed neutralizing antibodies against the SARS-Cov-2 virus, can donate plasma to treat severe/critical patients. Some reports have indicated promising results in a low number of patients who received convalescent plasma313,314, but conclusions cannot be drawn until several randomized studies and more patients are analyzed. In addition to the use of convalescence plasma, hyperimmune globulin therapy or monoclonal antibodies directed against the virus have also been proposed, and clinical assays are ongoing.

3.
Immunomodulation therapy. Intravenous immunoglobulins are aimed at blocking inflammation and preventing secondary infections312. This approach is being used with success in cases of Kawasaki syndrome in children.

4.
Cellular immunotherapy. To date, very little attention has been paid to the cellular immunotherapy approach in treatments of COVID-19, but several attempts may include the use of SARS-Cov-2-specific T and NK cells to trigger antiviral responses and autologous or allogenic Tregs to modulate inflammatory processes.

Future challenges in immunotherapy
Immunotherapy has been used for centuries, but only in recent years has this area expanded rapidly in several respects, mostly by the use of soluble elements (monoclonal antibodies and cytokines) and, more recently, with immune cells (cellular immunotherapy). There are many fields in which immunotherapy faces a range of challenges:

Vaccines
1. Researchers are working on reducing the number of injections by employing a combination of vaccines. Several current vaccines contain components from 3–6 pathogens in a single injection, and these are able to provide adequate protection against all of these pathogens315.

2. Researchers are developing more stable and durable vaccines. Improvements in the half-lives of vaccines, for example, by lyophilization, while maintaining immunogenicity is expected to reduce current problems, especially those involved in

uture challenges in immunotherapy
Immunotherapy has been used for centuries, but only in recent years has this area expanded rapidly in several respects, mostly by the use of soluble elements (monoclonal antibodies and cytokines) and, more recently, with immune cells (cellular immunotherapy). There are many fields in which immunotherapy faces a range of challenges:

Vaccines
1. Researchers are working on reducing the number of injections by employing a combination of vaccines. Several current vaccines contain components from 3–6 pathogens in a single injection, and these are able to provide adequate protection against all of these pathogens315.

2. Researchers are developing more stable and durable vaccines. Improvements in the half-lives of vaccines, for example, by lyophilization, while maintaining immunogenicity is expected to reduce current problems, especially those involved in the transportation of vaccines to remote areas316. In this respect, nanotechnology can help in the design of more stable vaccines that lead to slow antigen release and improved immunogenicity317.

3. Researchers are working on vaccines that confer protection against all serotypes of a specific pathogen (universal). This outcome is especially important for pathogens with high variability (such as the influenza virus). Researchers are designing vaccines that can protect against several variants by using common regions that can induce protective immune responses to all or most of the variants318.

4. Researchers are developing alternative routes of administration (e.g., oral, inhaled, intranasal, skin, rectum, vagina) as substitutes for intramuscular or subcutaneous injections. One of the problems to be solved is the immune tolerance developed to elements delivered by the oral route, but some vaccines are already effectively administered by this route (such as the oral polio, cholera, typhoid fever and rotavirus vaccines). The intranasal route has also proven effective for some vaccines (nasal influenza vaccine), and vaccines administered through other routes are under investigation.

5. Researchers are seeking the early protection of newborns319. Newborns are very susceptible to infections due to their immature immune system320. Moreover, the protection exerted by maternal antibodies transferred through the placenta during pregnancy against some pathogens interferes with the development of the newborn’s own immune response. Greater knowledge on ways to activate the immature immune system early will enable the development of vaccines for newborns. Moreover, immunization of pregnant women may help to enhance neonatal protection against several pathogens321.

6. Researchers are developing new and more effective vaccines. This effort is crucial for very prevalent pathogens such as Mycobacteria tuberculosis, HIV virus or plasmodium falciparum. Although there are treatments against these pathogens, most are not curative—as in the case of HIV; prevention is the best way to stop their spread.

7. Researchers are working to address emerging pandemics. In the case of new pathogens, such as SARS-Cov-2, which has produced a recent global outbreak, effective vaccines are urgently required322. New technologies for vaccine formulations and routes of administration, the identification of immune-related factors of protection and modifications to the governmental regulatory and approval process for vaccines for emerging pathogens are challenges that must be faced to achieve a rapid vaccination procedure for outbreaks. Hundreds of vaccines against SARS-Cov-2 (using different strategies such as live attenuated or inactivated pathogens, viral vector-based, viral RNA, DNA, recombinant proteins, peptides, etc.)323 are now under development, and some are in clinical trials. However, the need to develop a new vaccine in a short period of time should not negate the main principles of vaccination use: safety and immune protection.

8. Researchers are working on genetic (RNA, DNA) vaccines because they have great advantages, including no requirement for growing a pathogen. Genetic vaccines can be obtained in a much shorter time, with much faster and safer production processes, and can be transported much more easily. However, the immunogenicity of these vaccines must be improved, and other problems need be avoided, such as the potential deleterious effects of integrating vaccine sequences into cells324.

9. Researchers are developing safer and more powerful adjuvants. Many years ago, the only adjuvant authorized for vaccines was aluminum hydroxide (alum), but currently, several adjuvants are on the market325. The use of ligands that activate the innate immune response, such as those linked to TLRs or nanostructures with adjuvant effects, is currently under study.

10. Researchers are boosting trained immunity, a new concept related to the innate immune memory-like described for NK cells (expansion) and macrophages (epigenetic modifications). Knowledge of how to handle trained immunity will enable better vaccine design and more effective secondary responses326.

11. Researchers are seeking to eradicate diseases from the earth. The greatest challenge, eradicating disease is possible in the short term for some pathogens, such as poliovirus. Very few cases of polio have been recently reported, and these reports came from only three countries; therefore, it is feasible that this disease can be eradicated in the near future.

12. Advances are challenged by the anti-vaccine movement. Paradoxically, there are people who doubt the beneficial effects of vaccines, and they are putting the health of their own children and society in general at risk327. The effectiveness of community protection conferred through vaccinated people is disrupted by decreased numbers of immunized persons. This lesser coverage enables pathogens to infect the most susceptible people, such as small children, elderly patients and those who cannot be vaccinated due to certain pathologies or because they are undergoing immunosuppression treatment. Thus, news about the return of illnesses that were nearly forgotten, such as tetanus in Italy (the first case in 30 years), the death of a child in Catalonia from diphtheria, or the exponential increase of measles cases (already counted in the thousands) worldwide328, should make parents think carefully about the risks of not protecting children by vaccines. The World Health Organization (https://www.who.int/topics/vaccines/en/) argues that anti-vaccine movements can roll back all the achievements thus far in this field and have cited this issue as one of the main challenges to be resolved. Addressing the anti-vaccine movement requires a coordinated effort of professionals to inform parents adequately and perhaps other types of coercive measures that some countries are already applying (financial fines, denial of access to public assistance in childcare units, removal of authorization to travel/live in some countries, new laws, and so on).

Antibodies and cytokines
Immunotherapy with monoclonal antibodies has been a true revolution for many pathologies, as has the use of certain cytokines and recombinant fusion proteins. It is therefore predicted that these approaches may have a bright future, and regulatory agencies are expected to authorize many more mAb-based therapies in the coming years, especially given the good results obtained in clinical trials. Complete antibodies or those modified to increase their functionality or decrease their immunogenicity, combinations of antibodies and cytokines, antibody fragments, etc., are only some of the many possibilities for this type of product, which will expand the range of therapeutic options.

One of the main problems regarding the use of antibodies in therapy, especially in cancer, is based on their often unpredictable efficacy. Large variability in terms of remission and durable clinical benefits between patients is observed (for example, in the antitumoral responses by antibodies directed to the checkpoint inhibitors). Thus, the main challenge is to understand the situations in which an antibody will have the desired effect. It is crucial to find validated biomarkers (with predictive and/or prognostic value) that can help to stratify or select patients for the best immunotherapy. A better understanding is also required for tumor heterogeneity, resistance to some drugs and immunosuppressive microenvironments329. An in-depth immunological study, together with a personalized approach, is certainly the way to improve the success of these types of therapies.

In combination with conventional therapies (radiotherapy, chemotherapy, and surgery), other immunotherapeutic drugs or cellular immunotherapies can also help to maximize the efficacy of this immunotherapy, but increases in toxicity will be another challenge to face.

Pathogens
The use of oncolytic viruses (OVs), bacteriophages that selectively infect bacteria, modified pathogens for vaccines or for antitumor immuno-activation, and the manipulation/ modification of the microbiota are some of the therapies that are being considered.

OVs are designed to kill tumor cells and to activate the immune system against those cells. However, many of OVs have shown limited therapeutic effects when applied in monotherapy; therefore, much more work is required to improve their systemic antitumor effects and avoid the attenuation of the virus, which limits the viral replication. Several obstacles, such as low viral delivery and spread, resistance to therapy and antiviral immunity, have been observed330. Thus, the main challenges with oncolytic viruses are addressed by improving their antitumoral efficacy, including the optimization of viral delivery, the development of OVs engineered to activate the immune system (e.g., by releasing cytokines), and their use as adjuvant therapies or in combination with other immunotherapeutic agents, such as immunomodulators331.

Regarding gut microbiota manipulation as a therapeutic approach, fecal microbiota transplantation is an effective therapy for recurrent Clostridium difficile infection332 and is now being investigated for other indications, such as inflammatory bowel disease and cancer. Some of the challenges facing microbiome transplantation are the lack of precise knowledge about the complete microbiome and the mechanisms of action involved in its therapeutic capacity, the large variability of its effectiveness and the external factors that affect it. More studies are centered on understanding how to manipulate bacterial colonies, the discovery of therapeutic molecules, nutrient competitions, etc., that are required for successful application. The best type of therapy (either individual or the combination of bacteria) is also under debate, along with how to reach the market by translating this individualized therapy into commercial scale products. The safety and potential adverse long-term effects are also being assessed.

Other components (nanomaterials and small molecules)
Nanomaterials. To obtain approval for the use of other elements from incipient fields, such as the use of different types of nanostructures, either alone or in combination with other immunotherapies, it is important to resolve certain issues. In the case of nanoparticle use, a better understanding of the interaction between nanomaterials and biological media; nanoparticle biodistribution, metabolism and biocompatibility; and the reproducibility of the synthesis and scaled up production of nanomaterials are among the issues to address.

Small molecules. A greater knowledge of several molecules involved in the immune system has led to the development of new therapeutic agents, which have been synthesized by traditional chemistry and block or activate intracellular signaling. The low cost of production of these molecules, along with the scaling and reproducibility of small-molecule batches, has attracted the attention of pharmaceutical companies interested in a whole set of new immunomodulatory drugs. A better understanding of the mechanism of action of small-molecule-based drugs and proof that they offer higher efficacy than existing therapies, either in monotherapy or in combination therapy, are challenges that face those seeking to engineer new types of targeting molecules.

Cellular immunotherapy
To date, cellular immunotherapy has been an individualized therapy with high production costs, and it requires the involvement of multidisciplinary groups in hospitals. A real challenge in the field of cellular immunotherapy is the acquisition of universal off-the-shelf cell therapies to replace those currently made to order in a very personalized manner. The development of universal cells, for example, in the case of CAR T-cell therapy, would increase the number of patients who could benefit from this treatment at thus reduce the costs.

Other challenging aspects of cellular immunotherapy are the life-threatening toxicity of induced and their lack of effect on solid tumors, which is mostly due to the immunosuppressive tumor microenvironment. This approach requires new strategies to overcome these difficulties. In addition to cancer, cellular immunotherapy has a long history of use against autoimmunity, infectious diseases, allergies and transplantation rejection. It is also important to find biomarkers for prognosis/prediction that can help to optimize this method. Other therapies that involve the use of activated NK cells, tumor-infiltrating lymphocytes, vaccination with dendritic cells, etc., are having partial clinical success. Similar to other treatments, these approaches require further study, but it is feasible that they may become reality in the near future.

Conclusions
Greater knowledge of the immune system, especially concerning the variety of cellular and humoral components and the close regulation among them, the interaction with other systems or with elements such as the microbiota, will allow the development of new types of therapies that may be safer, more effective and specific but with much lower toxicity than found in current therapies. This long journey has been possible due to the efforts of numerous researchers (throughout the centuries), who have contributed with their work, creativity, successes and failures to advance our knowledge of the immune system, cellular components, membrane markers, interactions, signaling pathways and many more aspects. This great combined effort has paved the way for the achievements that are currently being realized.
curncman
Posts: 496
Joined: Fri Jun 26, 2020 8:27 am

Network and systems based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

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Network and systems based re-engineering of dendritic cells with non-coding RNAs for cancer immunotherapy

https://www.biorxiv.org/content/10.1101 ... 47v1?rss=1

Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that induce and regulate adaptive immunity by presenting antigens to T cells. Due to their coordinative role in adaptive immune responses, DCs have been used as cell-based therapeutic vaccination against cancer. The capacity of DCs to induce a therapeutic immune response can be enhanced by re-wiring of cellular signalling pathways with microRNAs (miRNAs). Since the activation and maturation of DCs is controlled by an interconnected signalling network, we deploy an approach that combines RNA sequencing data and systems biology methods to delineate miRNA-based strategies that enhance DC-elicited immune responses. Through RNA sequencing of IKKβ-matured DCs that are currently being tested in a clinical trial on therapeutic anti-cancer vaccination, we identified 44 differentially expressed miRNAs. According to a network analysis, most of these miRNAs regulate targets that are linked to immune pathways, such as cytokine and interleukin signalling. We employed a network topology-oriented scoring model to rank the miRNAs, analysed their impact on immunogenic potency of DCs, and identified dozens of promising miRNA candidates with miR-15a and miR-16 as the top ones. The results of our analysis are incorporated in a database which constitutes a tool to identify DC-relevant miRNA-gene interactions with therapeutic potential (www.synmirapy.net/dc-optimization).
curncman
Posts: 496
Joined: Fri Jun 26, 2020 8:27 am

In vivo targeting of DNA vaccines to dendritic cells via the mannose receptor induces long‐lasting immunity against mel

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In vivo targeting of DNA vaccines to dendritic cells via the mannose receptor induces long‐lasting immunity against melanoma

https://www.x-mol.com/paper/1304099941663346688

Herein, we report on an effective, C‐type lectin mannose receptor (MR)‐selective in vivo DC‐targeting lipid nanoparticles (LNPs) of a novel lipid‐containing mannose‐mimicking di‐shikimoyl‐ and guanidine head‐group and two n‐hexadecyl hydrophobic tails (DSG). Subcutaneous administration of LNPs of DSG/p‐CMV‐GFP complex showed a significant expression of green fluorescence protein in the CD11c + DCs of the neighboring lymph nodes compared to the control LNPs of BBG/p‐CMV‐GFP complex. Mannose receptor‐facilitated in vivo DC‐targeted vaccination (s.c.) with the electrostatic complex of LNPs of DSG/pCMV‐MART1 stimulated long‐lasting (270 days post B16F10 tumor challenge) anti‐melanoma immunity under prophylactic conditions. Remarkably, under therapeutic settings vaccination (s.c.) with the LNPs of DSG/pCMV‐MART1 complex significantly delayed melanoma growth and improved the survival of mice with melanoma. These findings demonstrate that this non‐viral delivery system offers a resilient and potential approach to deliver DNA vaccines encoding tumor antigens to DCs in vivo with high efficacy.
curncman
Posts: 496
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Brink Biologics Announces License Agreement with Global Healthcare Company Fresenius Kabi SwissBioSim GmbH

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Brink Biologics Announces License Agreement with Global Healthcare Company Fresenius Kabi SwissBioSim GmbH

https://apnews.com/e038a353be0e4950b58fe9065328d561

SAN DIEGO--(BUSINESS WIRE)--Sep 10, 2020--

Brink Biologics, Inc. (“Brink”), a NantKwest, Inc. (NASDAQ: NK) affiliate and exclusively-licensed distributor of NantKwest’s proprietary off-the-shelf NK-92® natural killer cells in certain fields, announces the licensing of its next-generation natural killer-based bioanalytical testing solution to Fresenius Kabi SwissBioSim GmbH (“Fresenius”), a Switzerland-based global healthcare company focusing on autoimmune diseases and oncology.

Brink Biologics offers a variety of GLP and research-grade NK-92® based cell lines as part of its Neukopanel® portfolio of products for laboratory testing applications. Neukopanel® includes discovery, translational and developmental research as well as commercial lot release testing of clinical products. Brink products are utilized widely by large pharmaceuticals and biotechnology companies to support products ranging from anti-viral and dendritic cell vaccines, therapeutic monoclonal antibodies and biosimilars, bi- and tri-specific fusion proteins, cytokines, natural killer cell checkpoint inhibitors and other biologic products.

The laboratory use of live natural killer cell cultures for functional assays, such as antibody dependent cellular cytotoxicity, antibody-dependent cell-mediated viral inhibition and cytokine release assays, most closely approximates what one would actually see in target patient populations. Of all the sources of natural killer cells, Brink’s NK-92® natural killer cells are considered to be the gold standard when it comes to providing greater assay consistency and reproducibility, testing scalability, and reduced labor time and costs for laboratory scientists and technicians. These features give a competitive edge to companies licensed to use Brink’s NK-92® products.

Fresenius has joined the growing list of leading biotechnology companies that are using Brink’s NK-92® cell line for laboratory based bioanalytical testing.

“Since our proprietary NK-92® cell line provides unique advantages to commercial and academic researchers as well as commercial manufacturers, we are committed to making our bioanalytical testing solutions widely available to the public through standard licensing agreements using market-driven terms and conditions,” said Barry Simon, M.D., CEO of Brink Biologics and President of NantKwest. “A growing number of commercial large pharma, biotech and device companies are joining scores of academic researchers who have accessed our NK-92 based cell lines to facilitate their internal activities. Our affiliate, NantKwest, has manufactured more than three trillion GMP-grade NK-92® cells and hundreds of doses of clinical product have been administered to patients in clinical trials since 2017. This positions NK-92® well to grow as a leading functional cell-based testing platform to complement its role as a leading immunotherapy platform, currently under development. We are pleased to make our testing solution available to Fresenius to facilitate their research and development endeavors.”
trader32176
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Re: What's The Future of Cancer Immunotherapy? World Renowned Cancer Expert Shares His Perspective

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New immunotherapy to beat cancer

9/11/20

https://medicalxpress.com/news/2020-09- ... ancer.html

Sophie Lucas (University of Louvain de Duve Institute) and her team have succeeded in neutralizing a molecule that blocks the immune system against cancer. The UCLouvain scientists discovered that this new immunotherapy increases the action of another well-known but not always effective immunotherapy, and that it makes tumor regression possible. This very promising discovery in the fight against cancer is published in the journal Nature Communications.

Cancer immunotherapy is the manipulation of the immune responses naturally present in the human body to fight cancer. Often, these immune responses are blocked by cells or molecules that prevent them from killing cancer cells, and the tumor is able to establish itself and grow.

In 2004, Sophie Lucas, researcher at the University of Louvain de Duve Institute, began studying the blocking of immune defenses in tumors in order to understand the functioning of cells that are said to be "immunosuppressive" (which block the body's immune responses). The goal was to identify and remove them, thus stimulating antibodies to act against the tumor. The identified culprits are regulatory T lymphocytes (Tregs): highly immunosuppressive cells in cancer patients. In 2009, Prof. Lucas discovered GARP, a molecule located on the surface of Tregs.

In 2018, Prof. Lucas finally managed to understand the role of GARP: the molecule acts as a messenger for Tregs, by sending signals that block immune responses. She is developing a tool (anti-GARP antibodies) to neutralize and prevent the messenger from sending its blocking signals. This important discovery was published in the journal Science.

In August 2020, Nature Communications published the results of the first tests carried out by Prof. Lucas and her team. The tests are promising: The scientists succeeded in neutralizing Tregs in cancerous mice using anti-GARP antibodies. If the messenger is neutralized, immune responses are not blocked and can again eliminate cancer cells. The tumor regresses quickly provided the anti-GARP antibodies are combined with another proven immunotherapy (anti-PD1 antibodies). Thus the UCLouvain team combines two complementary immunotherapy approaches, acting in different ways on the immune system, to increase the effectiveness of cancer treatment. And it works!

Conducting these same tests on humans could eventually provide a more effective therapeutic solution in the fight against cancer.
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Effective cancer immunotherapy further linked to regulating a cell 'suicide' gene

https://medicalxpress.com/news/2020-09- ... -cell.html

Johns Hopkins Medicine researchers have added to evidence that a gene responsible for turning off a cell's natural "suicide" signals may also be the culprit in making breast cancer and melanoma cells resistant to therapies that use the immune system to fight cancer. A summary of the research, conducted with mice and human cells, appeared Aug. 25 in Cell Reports.

When the gene, called BIRC2, is sent into overdrive, it makes too much, or an "overexpression," of protein levels. This occurs in about 40% of breast cancers, particularly the more lethal type called triple negative, and it is not known how often the gene is overexpressed in melanomas.

If further studies affirm and refine the new findings, the researchers say, BIRC2 overexpression could be a key marker for immunotherapy resistance, further advancing precision medicine efforts in this area of cancer treatment. A marker of this kind could alert clinicians to the potential need for using drugs that block the gene's activity in combination with immunotherapy drugs to form a potent cocktail to kill cancer in some treatment-resistant patients."Cancer cells use many pathways to evade the immune system, so our goal is to find additional drugs in our toolbox to complement the immunotherapy drugs currently in use," says Gregg Semenza, M.D., Ph.D., the C. Michael Armstrong Professor of Genetic Medicine, Pediatrics, Oncology, Medicine, Radiation Oncology and Biological Chemistry at the Johns Hopkins University School of Medicine, and director of the Vascular Program at the Johns Hopkins Institute for Cell Engineering.

Semenza shared the 2019 Nobel Prize in Physiology or Medicine for the discovery of the gene that guides how cells adapt to low oxygen levels, a condition called hypoxia.

In 2018, Semenza's team showed that hypoxia essentially molds cancer cells into survival machines. Hypoxia prompts cancer cells to turn on three genes to help them evade the immune system by inactivating either the identification system or the "eat me" signal on immune cells. A cell surface protein called CD47 is the only "don't eat me" signal that blocks killing of cancer cells by immune cells called macrophages. Other cell surface proteins, PDL1 and CD73, block killing of cancer cells by immune cells called T lymphocytes.

These super-survivor cancer cells could explain, in part, Semenza says, why only 20% to 30% of cancer patients respond to drugs that boost the immune system's ability to target cancer cells.

For the current study, building on his basic science discoveries, Semenza and his team sorted through 325 human genes identified by researchers at the Dana Farber Cancer Institute in Boston whose protein products were overexpressed in melanoma cells and linked to processes that help cancer cells evade the immune system.

Semenza's team found that 38 of the genes are influenced by the transcription factor HIF-1, which regulates how cells adapt to hypoxia; among the 38 was BIRC2 (baculoviral IAP repeat-containing 2), already known to prevent cell "suicide," or apoptosis, in essence a form of programmed cell death that is a brake on the kind of unchecked cell growth characteristic of cancer.

BIRC2 also blocks cells from secreting proteins that attract immune cells, such as T-cells and natural killer cells.

First, by studying the BIRC2 genome in human breast cancer cells, Semenza's team found that hypoxia proteins HIF1 and HIF2 bind directly to a portion of the BIRC2 gene under low oxygen conditions, identifying a direct mechanism for boosting the BIRC2 gene's protein production.

Then, the research team examined how tumors developed in mice when they were injected with human breast cancer or melanoma cells genetically engineered to contain little or no BIRC2 gene expression. In mice injected with cancer cells lacking BIRC2 expression, tumors took longer to form, about three to four weeks, compared with the typical two weeks it takes to form tumors in mice.

The tumors formed by BIRC2-free cancer cells also had up to five times the level of a protein called CXCL9, the substance that attracts immune system T-cells and natural killer cells to the tumor location. The longer the tumor took to form, the more T-cells and natural killer cells were found inside the tumor.

Semenza notes that finding a plentiful number of immune cells within a tumor is a key indicator of immunotherapy success.

Next, to determine whether the immune system was critical to the stalled tumor growth they saw, Semenza's team injected the BIRC2-free melanoma and breast cancer cells into mice bred to have no functioning immune system. They found that tumors grew at the same rate, in about two weeks, as typical tumors. "This suggests that the decreased tumor growth rate associated with loss of BIRC2 is dependent on recruiting T-cells and natural killer cells into the tumor," says Semenza.

Finally, Semenza and his team analyzed mice implanted with human breast cancer or melanoma tumors that either produced BIRC2 or were engineered to lack BIRC2. They gave the mice with melanoma tumors two types of immunotherapy FDA-approved for human use, and treated mice with breast tumors with one of the immunotherapy drugs. In both tumor types, the immunotherapy drugs were effective only against the tumors that lacked BIRC2.

Experimental drugs called SMAC mimetics that inactivate BIRC2 and other anti-cell suicide proteins are currently in clinical trials for certain types of cancers, but Semenza says that the drugs have not been very effective when used on their own.

"These drugs might be very useful to improve the response to immunotherapy drugs in people with tumors that have high BIRC2 levels," says Semenza.
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New 3-D printed hydrogels for T-cell growth for cancer immunotherapy

https://medicalxpress.com/news/2020-08- ... ancer.html

A team with the participation of researchers from the ICMAB has designed new hydrogels for culturing T-cells or T-lymphocytes, cells of the immune system that are used in cancer immunotherapy with the capacity to destroy tumor cells. These hydrogels can mimic lymph nodes in which T-cells reproduce and provide high rates of cell proliferation. Scientists hope to be able to bring this new technology to hospitals soon. The first details are published in the journal Biomaterials.

The 3-D hydrogels are made of polyethylene glycol (PEG), a biocompatible polymer widely used in biomedicine, and heparin, an anticoagulant agent. In this case, the polymer provides the structure and mechanical properties necessary for T-cells to grow, while heparin is used to anchor different biomolecules of interest, such as cytokine CCL21, a protein present in the lymph nodes that has a major role in cell migration and proliferation.

Adoptive cell therapy

Cancer immunotherapy is based on using and strengthening the patients' immune system so that it recognizes and fights tumor cells without damaging healthy tissues. One such possible treatment, adoptive cell therapy, consists of extracting T-cells from patients, modifying them to make them more active, making numerous copies of them, and injecting them back into patients.

"This personalized therapy, although still very novel, seems to have more lasting effects than current oncological therapies, thanks to some T-lymphocytes that are capable of conferring immunity over time," says researcher Judith Guasch from the Institute of Materials Science of Barcelona (ICMAB-CSIC). "Its application is limited by the current cell culture media, since they are not effective enough for the proliferation and growth of a relevant amount of therapeutic T-cells in a short time and in an economically viable way."
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A blood test could predict who benefits from immunotherapy

https://medicalxpress.com/news/2020-08- ... erapy.html

A test which detects changing levels of tumor fragments in the blood may be an easy, non-invasive and quick way to predict who will benefit from immunotherapy, a treatment option for advanced cancers.

Although immunotherapy has been shown to shrink tumors and prolong survival for patients for whom other treatments have failed, about 20-30% of patients benefit from it. Clinicians don't yet know ahead of time who this subset of patients is.

Understanding this is crucial, since immunotherapy can have severe side effects in a small percentage of patients, and knowing whether to begin or continue would be helpful for patients weighing different treatment options.

A team of Princess Margaret Cancer Centre scientists and clinicians addressed this question with a novel study evaluating various cancer patients' response to a specific immunotherapy drug via a customized test based on each patient's tumor profile.

They found that individual response to treatment can be predicted within weeks, based on increasing or decreasing levels of DNA fragments which are shed from the tumor into the blood.

Genomic testing with powerful new technologies can detect the same genetic mutations in the fragments circulating in the blood as in the actual tumor. These fragments are called circulating DNA or ctDNA.

Specifically, the study found that a decrease in these circulating tumor DNA fragments at six—seven weeks after treatment with the immunotherapy drug pembrolizumab was associated with a beneficial response to the drug and longer survival.

The study, "Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab", is published in Nature Cancer, August 3, 2020.

Dr. Lillian Siu, a Senior Scientist and medical oncologist at the Princess Margaret, BMO Chair in Precision Cancer Genomics, and a co-senior author, noted that the study is one of the first studies across a broad spectrum of tumors to show that measuring levels of ctDNA could be useful as a predictor of who responds well to immunotherapy.

"It's like a molecular CT scan that gives us a molecular dimension, an added layer of information to know whether a tumor is growing or not, " she says, "That's why this is so exciting. It helps to predict early on what may happen over time.

"Although important, computerized tomography (CT) and other scans alone will not tell us what we need to know quickly or accurately enough."

Dr. Scott Bratman, who is first author and a radiation oncologist and Senior Scientist at Princess Margaret and Associate Professor of Radiation Oncology and Medical Biophysics, University of Toronto, points out that it may take many months to detect whether a tumor is shrinking with various imaging scans.

"New next-generation sequencing technologies can detect and measure these tiny bits of cellular debris floating in the blood stream accurately and sensitively, allowing us to pinpoint quite quickly whether the cancer is active."

The prospective study analyzed the change in ctDNA from 74 patients, with different types of advanced cancers, being treated with pembrolizumab.

In order to customize or personalize the test, all the genes from the tumor biopsy tissue of each patient were sequenced or decoded at Princess Margaret, with specific attention to the mutations that occur in cancer. These cancer mutations ranged from dozens to tens of thousands of mutations per tissue sample, differing according to cancer type.

Sixteen genetic mutations for each patient were then selected for a specific test to be developed and customized to detect personalized ctDNA of each patient via a simple blood sample.

"When we looked at all 20,000 genes in each cancer, the range of mutations in different individuals was huge due to the many different cancer types in the study," says Dr. Trevor Pugh, a co-senior author, Senior Scientist at Princess Margaret and Associate Professor, Dept. of Medical Biophysics, University of Toronto, and Director of Genomics, Ontario Institute for Cancer Research.

"The novelty is that, rather than taking a one-size-fits-all approach, we designed a personalized blood test for each person based on their own cancer's mutation list."

Of the 74 patients, 33 had a decrease in ctDNA levels from their original baseline levels to week six to seven after treatment with the drug. These patients had better treatment responses and longer survival. Even more striking was that all 12 patients who had clearance of the ctDNA to undetectable levels during treatment were still alive at a median follow-up of 25 months.

Conversely, a rise in ctDNA levels was linked to a rapid disease progression in most patients, and poor survival.

"Few studies have used a clinical biomarker across different types of cancers," says Dr. Siu, who is also the Clinical Lead for the Tumor Immunotherapy Program at the Princess Margaret and Professor of Medicine, University of Toronto, adding that "the observation that ctDNA clearance during treatment and its link to long-term survival is novel and provocative, suggesting that this biological marker can have broad clinical impact."

Mr. Azim Jamal, 71, was part of the study, and one of the patients who benefited from immunotherapy. He was diagnosed with throat cancer in 2016, and received radiation and targeted molecular therapy.

With limited response and the cancer spreading to his lungs, he then received immunotherapy over two years, beginning in 2017. As of July 2020, his disease is in remission, with no evidence of progression.

"It was a last resort, but I said yes immediately," he says when asked if he would like to participate in the immunotherapy clinical trial. "I want to enjoy life, I want to see my grandchildren, participate in my community and church. And I also appreciate the opportunity to participate in important research that could help others."

Serena Jamal-Esmail, his daughter who is also a nurse, says that seeing her father respond so well to the immunotherapy was "like a light...It had been so emotional, so scary. My kids will be able to remember their granddad. I can breathe again."

The prospective study is part of a larger flagship clinical trial, INSPIRE, which has enrolled more than 100 patients with head and neck, breast, ovarian, melanoma and other advanced solid tumors. Launched at Princess Margaret in 2016, the trial follows and tests patients at various stages of their treatment to pembrolizumab, a commonly used type of immunotherapy.

It also brings together researchers from many disciplines to investigate if specific genomic and immune biomarkers in patients may predict for response or resistance to the drug.
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Researchers discover the microbiome's role in attacking cancerous tumours

https://medicalxpress.com/news/2020-08- ... mours.html

Researchers with the Snyder Institute for Chronic Diseases at the Cumming School of Medicine (CSM) have discovered which gut bacteria help our immune system battle cancerous tumors and how they do it. The discovery may provide a new understanding of why immunotherapy, a treatment for cancer that helps amplify the body's immune response, works in some cases, but not others. The findings, published in Science, show combining immunotherapy with specific microbial therapy boosts the ability of the immune system to recognize and attack cancer cells in some melanoma, bladder and colorectal cancers.

Dr. Kathy McCoy, Ph.D., is a leading expert on the body's relationship with the microbiome. She and her team are focused on harnessing the power of the microbiome to improve health and treat diseases. McCoy says to harness and direct that power scientists need to better understand the role bacteria play in regulating the immune system.

"Recent studies have provided strong evidence that gut microbiota can positively affect anti-tumor immunity and improve the effectiveness of immunotherapy in treating certain cancers, yet, how the bacteria were able to do this remained elusive, " says McCoy, director of the International Microbiome Centre at the University of Calgary and principal investigator on the study. "We've been able to build on that work by showing how certain bacteria enhance the ability of T-cells, the body's immunity soldiers that attack and destroy cancerous cells."

First, the researchers identified bacterial species that were associated with colorectal cancer tumors when treated with immunotherapy. Working with germ-free mice, they then introduced these specific bacteria along with immune checkpoint blockade, a type of cancer immunotherapy. Research revealed that specific bacteria were essential to the immunotherapy working. The tumors shrank, drastically. For those subjects that did not receive the beneficial bacteria, the immunotherapy had no effect.

"We found that these bacteria produce a small molecule, called inosine," says Dr. Lukas Mager, MD, Ph.D., senior postdoctoral researcher in the McCoy lab and first author on the study. "Inosine interacts directly with T-cells and together with immunotherapy, it improves the effectiveness of that treatment, in some cases destroying all the colorectal cancer cells."

The researchers then validated the findings in both bladder cancer and melanoma. The next step in this work will be to study the finding in humans. The three beneficial bacteria associated with the tumors in mice have also been found in cancers in humans.

"Identifying how microbes improve immunotherapy is crucial to designing therapies with anti-cancer properties, which may include microbials," says McCoy. "The microbiome is an amazing collection of billions of bacteria that live within and around us everyday. We are in the early stage of fully understanding how we can use this new knowledge to improve efficacy and safety of anti-cancer therapy and improve cancer patient survival and well-being."
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Researchers ID new target in drive to improve immunotherapy for cancer

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

Researchers at the UCLA Jonsson Comprehensive Cancer Center and UCLA School of Dentistry have identified a potential new combination therapy to treat advanced head and neck squamous cell carcinoma, the most common type of head and neck cancer.

A study in mice found that using an anti-PD1 immunotherapy drug in combination with PTC209, an inhibitor that targets the protein BMI1, successfully stopped the growth and spread of the cancer, prevented reoccurrences and eliminated cancer stem cells. This is the first preclinical study to provide evidence that targeting BMI1 proteins enhances immunotherapy and eliminates cancer stem cells by activating antitumor immunity.

Immunotherapies using PD1 blockade have transformed the way people with difficult cancers are treated. Currently, PD1 blockade combined with chemotherapy is approved for recurrent or metastatic head and neck cancer, giving people whose disease would have otherwise been seen as a death sentence another option. However, response rates are not very high and response duration is relatively short, indicating that this type of cancer might be resistant to PD1 blockade.

To help overcome immunotherapy resistance, UCLA researchers have been studying the role of cancer stem cells and the protein BMI1. Growing evidence suggests cancer stem cells might be responsible for such resistance, as well as for relapse or reoccurrence, and BMI1, which functions in several cancers, including head and neck, has been found to control cancer stem cells' self-renewal. Targeting cancer stem cells may be critical for improving the efficacy of immunotherapy and preventing tumor relapse.

The team used a mouse model of head and neck squamous cell carcinoma that fully mimicked human cancer development and metastasis, allowing them to perform lineage tracing of BMI1-positive cancer stem cells in an undisturbed tumor immune microenvironment. They then tested whether BMI1 cancer stem cells could be eradicated by PD1 blockade-based combination therapy using both pharmacological and genetic inhibition of BMI1. They found that inhibiting BMI1 not only helped eliminate the BMI1 cancer stem cells but also enhanced PD1 blockade by activating tumor cell-intrinsic immunity, which inhibited metastatic tumor growth and prevented tumor relapse.

Many people with advanced head and neck cancers who are treated with PD1 blockade and chemotherapy eventually see their cancer return and become resistant to the therapy. This preclinical study provides an important foundation for developing a new PD1 blockade-based combination therapy with BMI1 inhibitors that have the potential to help overcome resistance to the immunotherapy.
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