A Company Launched into Oncology Immunotherapy Space

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strawpatch
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Joined: Sun Jun 28, 2020 11:40 am

A Company Launched into Oncology Immunotherapy Space

Post by strawpatch »

Just saw a company was started called Adendra, which will research the use of dendritic cell biology for cancer and autoimmune diseases. Is this the same field of science / clinical research TSOI is in?

If so, I see it as a good thing. When more players get into a space, it raises recognition of the field of research itself. So rather than seeing competition, it is seen as bringing the science more into the light for Industry.

https://www.prnewswire.com/news-release ... 38620.html

NEW YORK and LONDON, Dec. 7, 2021 /PRNewswire/ -- ATP (Apple Tree Partners), a leader in life sciences venture capital, today announced the launch of Adendra Therapeutics Ltd. ("Adendra"), a company that will discover and develop treatments for cancers and autoimmune diseases by applying new insights into regulation of adaptive immune responses by dendritic cells. Adendra is funded with a $53 (£40) million Series A investment from ATP and founded by ATP as a spin-out of breakthrough biology conducted at the Francis Crick Institute in London in the lab of immunologist Caetano Reis e Sousa, D.Phil., whose research on ways in which dendritic cells orchestrate immune responses to cell death has been published in leading scientific journals.

Adendra's proprietary technology is based on the work of Professor Caetano Reis e Sousa's Immunobiology Laboratory at The Francis Crick Institute in collaboration with Raj Mehta, Ph.D., an Entrepreneur-in-Residence (EIR) at ATP who has previously founded and led companies including GammaDelta Therapeutics (recently acquired by Takeda) and Revitope Oncology. Adendra aims to design and develop novel immunotherapies focused on modulation of dendritic and other immune cells to augment immunological control of cancer or curtail T cell-driven autoimmunity.
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TimGDixon
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Re: A Company Launched into Oncology Immunotherapy Space

Post by TimGDixon »

Hey Strawpatch,

You are correct that we are deeply invested in dendritic cell technology. Original stemvacs was what we call an autologous dendritic cell cancer immunotherapy. Autologous meaning self; we took blood from the patient and then treated that blood to produce immature dendritic cells we then cultured/matured/activated and gave back to the patient in a subcutaneous injection.

Our latest dendritic cell is allogenic and can be used universally in any patient whereas the 1st generation was patient specific. This new dendritic cell is much more than a dendritic cell - we produce this cell by starting with an induced pluripotent stem cell (iPSC) (we obtain them from cord blood) and splitting off the dendritic cell which we can then for example treat that cell with a peptide/amino acid (called transfection) that can be fined tuned specifically to the patients cancer stem cell (all solid tumors have an original cancer stem cell) and instead of targeting tumor mass we seek and destroy the root of the cancer - kill the cancer stem cell and the tumor fails to survive. However in this now 3rd generation of stemvacs we can also fuse to the cell another cell we make from that same iPSC called an endothelial cell (blood vessel) that expresses a certain protein that the immune system targets for suppression effectively starving the tumor of blood. Our collegaue and science team memeber Dr. Marincola is a pioneer of dendritic cell therapies and was on the original panel at FDA that approved it - I will let him tell you in his own words in video below - please listen to 53:10 which is about 3 minutes in which are worth everyone's time to listen to what Franco says...never say never...



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TimGDixon
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Re: A Company Launched into Oncology Immunotherapy Space

Post by TimGDixon »

A little history for you...and why we continue to pursue adoptive cell therapy using dendritic cells. This is highly technical but I have provided you all my references to support this position(I even threw in some extras after 156). As I said above we are now producing the 3rd generation cell that magnifies all of this because we can present the cell as a chimera, for example a DC loaded with the boris peptide (hey folks boris cancer stem cell known as CD133 is found in 82% of all solid tumors and we own the patents) on one side and an epithelial cell loaded with alpga-gal protein on the other side is our creation - our frankenstein - ITS ALIVE - this cell does not occur in nature, hence it is a true chimera(and we own all the patents for this too).

Cancer has historically been treated with surgery, radiation, chemotherapy, and hormone therapy. More recently, advances in understanding of the immune system’s role in cancer have led to immunotherapy becoming an important treatment approach. Cancer immunotherapy began with treatments that nonspecifically activated the immune system and had limited efficacy and/or significant toxicity. In contrast, new immunotherapy treatments can activate specific, important immune cells, leading to improved targeting of cancer cells, efficacy, and safety. Within the immunotherapy category, treatments have included cytokine therapies, antibody therapies, and adoptive cell therapies.

In 1986, interferon-alpha became the first cytokine approved for cancer patients. In 1992, interleukin-2, or IL-2, was the second approved cytokine in cancer treatment, showing efficacy in melanoma and renal cell cancer. IL-2 does not kill cancer cells directly, but instead nonspecifically activates and stimulates the growth of the body’s own T cells which then combat the tumor. Although interferon-a, IL-2, and subsequent cytokine therapies represent important advances in cancer treatment, they are generally limited by toxicity and can only be used in a limited number of cancers and patients.

After cytokines set the stage for immunotherapy, antibody therapies represented the next significant advance, with targeted specificity and a generally better-tolerated side effect profile. Monoclonal antibodies, or mAbs, are designed to attach to proteins on cancer cells, and once attached, the mAbs can make cancer cells more visible to the immune system, block growth signals of cancer cells, stop new blood vessels from forming, or deliver radiation or chemotherapy to cancer cells. The first FDA approved mAb specifically for cancer was Rituxan in 1997, and since then, many other antibodies have received approval, including Herceptin, Avastin, Campath, Erbitux, and Vectibix. More recently, antibodies have been conjugated with cytotoxic drugs to increase activity. The first approved antibody drug conjugate was Mylotarg in 2000, followed by Adcetris in 2011 and Kadcycla in 2013.

The next important advance has been the development of antibodies that target T cell checkpoint pathways, which are means by which cancer cells are able to inhibit or turn down the body’s immune response to cancer. These treatments have shown an ability to activate T cells, shrink tumors, and improve patient survival. In 2011, Yervoy became the first checkpoint inhibitor approved by the FDA. Recent clinical data from checkpoint inhibitors such as nivolumab and Keytruda have confirmed both the approach and the importance of T cells as promising tools for the treatment of cancer.

The current Protocol seeks to generate a novel type of immunotherapy, StemVacs, which is comprised of activated dendritic cells administered subcutaneously for the purpose of inducing an innate immune stimulation, which would allow for utilization of antigen specific antigens in future studies. StemVacs is administered as an autologous dendritic cell product in which progenitors of dendritic cells are induced to mature with a leukocyte lysate that is clinically used under the name “Transfer Factor” or “ACTIVEIMMUNE”. Currently, studies have been conducted by researchers at Therapeutic Solutions International, Inc. in conjunction with the Regenerative Medicine Institute, in which the ACTIVEIMMUNE formulation of Transfer Factor was standardized and demonstrated to possess immune modulatory effects.

Description of StemVacs product
The drug product is an autologous dendritic cell vaccine matured with transfer factor and administered subcutaneously for induction of NK activity and antigen-nonspecific immune modulation. Safety of dendritic cells generated using the GM-CSF and IL-4 protocol has been established in numerous clinical studies. Safety of systemic administration of transfer factor has previously been demonstrated in clinical studies. In the current proposal dendritic cells are washed prior to administration, thereby the dose of transfer factor administered to patients will be minimal.

Dendritic cells (DC)
Dendritic cells (DC) possess unique morphology similar to neuronal dendrites and were originally identified based on their ability to stimulate the adaptive immune system. Of importance to the field of tumor immunotherapy, dendritic cells appear to be the only cell in the body capable of activating naïve T cells [1].

The concept of dendritic cells instructing naïve T cells to differentiate into effector or memory cells is fundamental because it places the dendritic cell as the most powerful antigen presenting cell. This implies that for immunotherapeutic purposes dendritic cells do not necessarily need to be administered at high numbers in patients. One way in which dendritic cells have been described is as sentinels of the immune system that are patrolling the body in an immature state [2, 3].

Once DC are activated, by a stimulatory signal such as a Damage Associated Molecular Patterns (DAMPS) the DC then migrate into the draining lymph nodes through the afferent lymphatics. During the trafficking process, DC degrade ingested proteins into peptides that bind to both MHC class I molecules and MHC class II molecules. This allows the DC to: a) perform cross presentation in that they ingest exogenous antigens but present peptides in the MHC I pathway; and b) activate both CD8 (via MHC I) and CD4 (via MHC II). Interestingly, lipid antigens are processed via different pathways and are loaded onto non-classical MHC molecules of the CD1 family [4].

Clinical Experiences and Safety of DC Vaccination
The possibility of utilizing DC to stimulate immunity was made into reality in animal studies that took advantage of the ability of immature DC to potently phagocytose various antigens. If the antigens possessed DAMPs, or if DAMPs were present in the environment, the DC would mature and present the antigens, resulting in stimulation of potent T cell immunity. Accordingly, in the initial studies, immature DC were incubated with various antigens, subsequent to which a maturation signal (replicating natural DAMPs) was applied and the DC were injected into animals. Thus DC were utilized as a type of “cellular adjuvant”. Indeed, it was discovered that the classical adjuvants such as Fruend’s Adjuvant actually contained a high concentration of DAMPs, which resulted in the stimulation of local DC at vaccination site in vivo.

One of the first clinical applications of DC was prostate cancer. In an early reported, thirty three androgen resistant metastatic prostate cancer patients were treated with DC that were pulsed with peptides from a prostate specific antigen termed PMSA. Nine partial responders were identified based on NCPC criterial, plus 50% reduction of PSA. Four of the partial responders were also responders in the phase I study, with an average response duration of 225 days. Their combined average total response period was over 370 days. Five other responders in the secondary immunizations at the Phase II were nonresponders in the phase I study. Their average partial response period was 196 days. These data support the safety of follow-up infusion of DC that have been pulsed with tumor antigen derived peptide [5].

The same group published a subsequent paper on an additional 33 patients that had not received prior DC immunization in the Phase I. All subjects received six infusions of DC pulsed with PSM-P1 and -P2 at six week intervals without any treatment associated adverse events. Six partial and two complete responders were identified in the phase II study based on NPCP criteria, plus 50% reduction of prostate-specific antigen (PSA), or resolution in previously measurable lesions on ProstaScint scan [6]. The same group analyzed immune response in patients who had clinical remission or relapsed. A strong correlation was found between delayed type hypersensitivity response to the PSM-P1 and PSM-P2 and clinical response [7].

Another subsequent study utilized DC generated using GM-CSF and IL-4 but pulsed with PAP, another prostate antigen. Specifically, the PAP was delivered to the DC by means of generation of a PAP-GM-CSF fusion protein. Two intravenous infusions of the generated cells were performed one month apart in 12 patients with androgen resistant prostate cancer. The infusions were followed by three s.c. monthly doses of the fusion protein without cells. Treatment was well tolerated and circulating prostate-specific antigen levels dropped in three patients. Immune response to the fusion protein was observed, as well as to PAP [8].

In addition to prostate cancer, in which FDA approval has been granted for the Provenge drug, numerous trials have been conducted in a wide variety of cancers. All the trials demonstrated safety, without serious adverse effects of DC administration, as well as some degree of therapeutic efficacy. Trials have been conducted in melanoma [9-60], soft tissue sarcoma [61], thyroid [62-64], glioma [65-86], multiple myeloma ,[87-95], lymphoma [96-98], leukemia [99-106], as well as liver [107-112], lung [113-126], ovarian [127-130], and pancreatic cancer [131-133].

Transfer Factor
The concept of an immunologically acting “Transfer Factor” was originally identified by Henry Lawrence in a 1956 publication [134], in which he reported simultaneous transfer of delayed hypersensitivity to diphtheria toxin and to tuberculin in eight consecutive healthy volunteers who received extracts from washed leucocytes taken from the peripheral blood of tuberculin-positive, Schick-negative donors who were highly sensitive to purified diphtheria toxin and toxoid. The leucocyte extracts used for transfer contained no detectable antitoxin. The recipient subjects were Schick-positive (<0.001 unit antitoxin per ml. serum) and tuberculin-negative at the time of transfer. All the recipients remained Schick-positive for at least 2 weeks following transfer and in every case their serum contained less than 0.001 units antitoxin at the time when they exhibited maximal skin reactivity to toxoid. The “transfer factor” that was utilized was prepared by washing packed leukocytes isolated using the bovine fibrinogen method, and washing the leukocytes twice in recipient plasma. The washed leukocytes were subsequently lysed by 7-10 freeze-thaw cycles in the presence of DNAse with Mg++. Administration of the extract was performed intradermally and subcutaneously over the deltoid area.

Given that in those early days little was known regarding T cell specificity and MHC antigen presentation, the possibility that immunological information was transmitted by these low molecular weight transfer factors was taken seriously. Transfer factors of various sizes and charges were isolated, with some concept that different antigens elicited different types of transfer factors [135, 136]. Numerous theories were proposed to the molecular nature of transfer factor. Some evidence was that it constituted chains of antibodies that were preformed but subsequently cleaved [137]. Functionally, one of the main thoughts was that transfer factor has multiple sites of action, including effects on the thymus, on lymphocyte-monocyte and/or lymphocyte-lymphocyte interactions, as well as direct effects on cells in inflammatory sites. It is also suggested that the "specificity" of transfer factor is determined by the immunologic status of the recipient rather than by informational molecules in the dialysates [138].

Burger et al [139], used exclusion chromatography to perform characterization of transfer factor. The found that specific transferring ability of transfer factor in vivo was found to reside in the major UV-absorbing peak (Fraction III). Fraction III transferred tuberculin, candida, or KLH-reactivity to previously negative recipients. Fraction III from nonreactive donors was ineffective. When the fractions were tested in vitro, we found that both the mitogenic activity of whole transfer factor and the suppressive activity to mitogen activation when present in transfer factor was found in Fraction I. Fraction III contained components responsible for augmentation of PHA and PWM responses. In addition, Fraction III contained the component responsible for antigen-dependent augmentation of lymphocyte transformation. Fraction IV was suppressive to antigen-induced lymphocyte transformation.

In 1992 Kirkpatrick characterized the specific transfer factor at molecular level. The transfer factor is constituted by a group of numerous molecules, of low molecular weight, from 1.0 to 6.0 kDa. The 5 kDa fraction corresponds to the transfer factor specific to antigens. There are a number of publications about the clinical indications of the transfer factor for diverse diseases, in particular those where the cellular immune response is compromised or in those where there is a deficient regulation of the immune response. It has been demonstrated that the transfer factor increases the expression of IFN-gamma and RANTES, while decreases the expression of osteopontine. Using animal models it has been reported that transfer factor possesses activity against M. tuberculosis, and with a model of glioma with good therapeutic results. In the clinical setting studies have reported effects against herpes zoster, herpes simplex type I, herpetic keratitis, atopic dermatitis, osteosarcoma, tuberculosis, asthma, post-herpetic neuritis, anergic coccidioidomycosis, leishmaniasis, toxoplasmosis, mucocutaneous candidiasis, pediatric infections produced by diverse pathogen germs, sinusitis, pharyngitis, and otits media. All of these diseases were studied through protocols which main goals were to study the therapeutic effects of the transfer factor, and to establish in a systematic way diverse dosage schema and time for treatment to guide the prescription of the transfer factor [140].

Numerous descriptions exist of various conditions treated with transfer factor. The majority of protocols utilized similar production procedures, essentially lysis of leukocytes and extraction of the <10Kda fraction.

Kirkpatrick [141], described 5 anergic patients with chronic mucocutaneous candidiasis who were treated with transfer factor from donors possessing a positive delayed type hypersensitive reactions to Candida. In each recipient, the delayed skin reactions of the transfer factor donors appeared in the recipients, however no recipient developed reactivities not possessed by the donor. Prior to injection of transfer factor, in vitro stimulation of the patients' lymphocytes with antigens did not result in macrophage inhibitor factor production, however, after transfer factor this response was positive. Therapy with transfer factor alone did not have therapeutic benefit, however, in 2 patients treatment with amphotericin-B followed by transfer factor has produced cutaneous remissions of 18 months. This study is interesting in that it demonstrated what appeared to be transfer of immunity from a skin reaction perspective but not immunological clearing of disease. In a similar study, Rocklin [142], described 2 patients with chronic mucocutaneous candidiasis and a defect in cellular immunity. Both patients received a single injection of dialysable transfer factor from Candida-positive donors in an effort to reconstitute immunologic function. The transfer of cellular hypersensitivity was successful in one of the two patients and was monitored by skin tests and MIF production; however, the effect was temporary and did not change the clinical course of the patient's infection. The other patient did not respond either immunologically or clinically to transfer factor at this time, although she did respond subsequently to repeated doses of transfer factor and amphotericin B therapy. The same report described transfer factor from tuberculin-positive donors being used successfully to eradicate an infection in a patient with progressive primary tuberculosis and an acquired defect in cellular immunity. The patient had not responded clinically or bacteriologically after 7 1/2 months of antituberculous therapy, although the organism was shown to be sensitive in vitro to the drugs she was receiving. She received 6 doses of dialysable transfer factor over a 3-month period and during this time she responded clinically, bacteriologically and roentgenographically.

An investigation into a larger number of patients, Grob [143] described a series of cases in which 409 units of transfer factor was given to 45 patients. In their report they defined one unit of transfer factor as the cell extract originating from 1 - 2 x 10(9) leukocytes. Besides local pain and occasional fever no side effects were observed. Immune conversions and beneficial clinical effects were seen in 11 and 10 patients, respectively, out of 12 patients with chronic candidiasis. Immune conversion was also observed in patients with multiple sclerosis, while the clinical effects cannot yet be judged. The series also included patients with subacute sclerosing panencephalitis, HBAg-positive disorders, various immunodeficiency diseases, malignant malanoma and miscellaneous tumours. Immune conversion occurred only occasionally and the clinical effect was either non-existent or not judgeable.

In addition to immune deficiencies and bacterial infections, transfer factor has demonstrated activity in viral infections. Given the RNA containing component of transfer factor, it may be that transfer factor induced interferon alpha production, which in turn would be responsible, in part for potential antiviral activity. Pizza et al [144], described , 33 patients with low immune response to HSV antigens and suffering from herpes ocular infections were orally treated with HSV-specific transfer factor. Their relapse index was reduced from 20.1 before treatment to 0.51 after administration, with only 6/33 patients relapsing. In another study, 20 HSV-1 patients whose disease had been treated before with other therapeutic agents (including acyclovir) were administered transfer factor and used as their own controls in terms of quantification of remissions. Transfer factor was administered subcutaneously daily for 3 to 4 days during the acute phase of the disease, and subsequently at 15-day intervals for the first 6 months; followed by a continuation of monthly injections until the termination of the study period. In 6/20 patients there was a recurrence of the disease while receiving maintenance dosages of transfer factor. These patients were again given the full initial dosage schedule and reinstated again with the maintenance dosage. The results showed an important improvement in the response to transfer factor immune modulation therapy in that a statistically significant reduction in the frequency of recurrences within a one month period was observed [145].

Supporting these observations, Meduri et al [146], reported an open clinical trial in 134 patients (71 keratitis, 29 kerato-uveitis, 34 uveitis) suffering from recurrent ocular herpetic infections. The mean duration of the treatment was 358 days. The cell-mediated immune response to the viral antigens, evaluated by the lymphocyte stimulation test and the leucocyte migration test, was significantly increased by the transfer factor treatment. The total number of relapses was decreased significantly during/after transfer factor treatment, dropping from 832 before, to 89 after treatment, whereas the cumulative relapse index dropped, during the same period, from 13.2 to 4.17.

A more recent study compared transfer factor with acyclovir in treatment of varicella herpes simplex patients. A double blind clinical trial of transfer factor compared to acyclovir was carried out in which 28 patients. Treatment was administered for seven days and the patients were subsequently submitted to daily clinical observation for an additional 14 days. An analogue visual scale was implemented in order to record pain and thereby served as the clinical parameter for scoring results. The group treated with transfer factor was found to have a more favorable clinical course, P < or = 0.015. Laboratory tests to assess the immune profile of the patients were performed two days prior and 14 days after initial treatment. The results of these tests showed an increase in IFN-gamma levels, augmentation in the CD4+ cell population in the transfer factor treated group. These parameters were however insignificantly modified in patients receiving acyclovir [147].

Given the association between viruses and cancer, as well as the potent stimulation of the killer arm of the immune system by transfer factor, rationale was made to treat various malignancies with transfer factor [148]. Levin et al [149], described treatment of 18 patients with osteogenic sarcoma. Of these, 13 have had or are currently receiving injections of osteogenic sarcoma-specific dialyzable transfer factor derived from healthy donors. In three patients with very small lesions, cytotoxicity was high before amputation and decreased within 2 mo after removal of tumor. Cytotoxicity was low at time of diagnosis in all patients with large tumor masses. The cytotoxicity of the patients' lymphocytes increased after administration of tumor-specific transfer factor in all patients so treated. Patients receiving nonspecific transfer factor showed evidence of declining cell-mediated cytotoxicity. Tumor-specific transfer factor may produce an increase in cell-mediated cytotoxicity to the tumor in patients with osteogenic sarcoma. This possibility is suggested by the pain and edema that occurred in the area of the tumor in patients who had metastatic disease when therapy was started and by lymphocytic infiltrates in the tumor, as well as by the increase in cell-mediated cytotoxicity and the increase in percentage of active rosette-forming cells from subnormal to normal.

Ng et al reported a controlled study in which 6 patients with stage-IV Hodgkin's disease were given transfer factor prepared from patients with Hodgkin's disease in long remission. There was an apparent increase in cell-mediated immune responses as evidenced by a significant increase in the recipients' lymphocyte responses to phytohaemagglutinin stimulation. Three out of six patients converted to positive delayed-hypersensitivity tests [150].

In head and neck cancer a study examined 67 patients of which 40 have received immunologic transfer factor from a normal donor pool. Examination of these patients revealed that lymphocyte reactivity to nonspecific mitogrens is depressed in patients who have head and neck cancer to a much greater extent than is seen in patients with other types of tumors. Th T-lymphocyte levels increased in eight of 38 patients who received nonimmune transfer factor [151].

Krown et al [152], reported on 18 patients with advanced cancer were given subcutaneous injections of pooled dialyzable transfer factor from normal donors for periods of from 9 days to 6.5 months. Minor tumor regression was observed in only two patients. Treatment with transfer factor was associated with at least a temporary increase in delayed hypersensitivity reactions in 12 of 17 patients tested, including four patients who became responsive to 2,4-dinitrochlorobenzene. In general, in vitro tests of immune function were not changed after treatment with transfer factor except for levels of C1q, and/or C3, which were increased in 6 of 10 patients tested.

Wagner et al [153], ran a prospective randomized double-blind study of 60 patients with invasive cervical cancer, 32 were treated with transfer factor derived from leukocytes of the patients' husbands, and 28 were treated with placebo. Within the first 2 years after radical hysterectomy, five out of 32 transfer factor-treated patients and 11 out of 28 placebo-treated patients developed recurrence of malignancy. Excluding one further patient with intercurrent death this difference is significant. Subdividing the collectives, significant differences were found in patients aged below 35 years and in patients with stage I disease. Identical immune profiles were checked in leukocyte donors prior to leukophoresis and were serially checked in patients. Antigen-specific correlations were found between donors' and recipients' reactivities but not between donors' reactivity and recipient's course of the disease.

Whyte et al [154], Reported on a patient evaluation between 1976 and 1982, 63 patients who underwent pulmonary resection, mediastinal lymph node dissection, and, when indicated by the presence of mediastinal lymph node involvement, mediastinal irradiation were randomized into two groups. Group 1 (n = 28) received 1 mL of pooled transfer factor at 3-month intervals after operation; group 2 (n = 35 ) served as controls and received saline solution. There were no statistically significant differences between the two groups with respect to age, sex, tumor histology, stage of disease, or extent of resection. One patient was lost to follow-up at 96 months; follow-up was complete in all others through July 1990. In patients receiving transfer factor, the 2-, 5-, and 10-year survival rates were 82%, 64%, and 43% respectively, whereas in controls they were 63%, 43%, and 23%. Survival in patients receiving transfer factor was consistently better than in those receiving placebo. Furthermore, survival in patients receiving transfer factor was greater at all stages of disease for both adenocarcinoma and squamous cell carcinoma. Although these long-term results were not statistically significant using survival analysis with covariates (p = 0.08), they confirm our previously reported short-term findings suggesting that administration of transfer factor, either through nonspecific immune stimulation, enhancement of cell-mediated immunity, or an as yet undefined mechanism, can improve survival in patients with bronchogenic carcinoma.

Subsequent studies, even from as early as the 1970s reported that transfer factor lacks antigen specificity. For example, Dupont et al [155], reported treatment of patients with transfer factor produced by the following means: a) 450 ml of healthy donor blood was drawn; b) buffy coat leukocytes (1.6 x 10(9)) were collected and concentrated into 1.6 ml of packed cells; c) cells were then diluted in 4 ml saline and underwent 10 freeze-thaw cycles; d) Mg++ and DNAse was added for 30 min and incubated at 37 Celsius; e) the cell lysate was dialyzed against 500 ml of distilled water for 2 day and redialyzed again using the same procedure; f) the dialysate was lyophilized and stored at – 20 Celsius, before use it was dissolved using a 0.45 micron filter. The authors reported evidence for nonspecificity in the effect of transfer factor on mixed lymphocyte culture reactivity. The data suggest that in patients with immunodeficiency disease a maturation of lymphocytes may lead to a generalized increased immune responsiveness. More profoundly, the data showed that transfer factor may induce changes in the expression of histocompatibility determinants. We observed changes in the expression of determinants capable of stimulating in the mixed lymphocyte culture reaction as well as an increase in the capacity of lymphocytes to respond. A subsequent paper also supported the concept that transfer factor may induce maturation of recipient immune cells in an antigen non-specific manner [156].

More recent studies have supported the concept that transfer factor may not act as the original notion of “transferring immunity” but as a non-specific immune modulator. One possibility is that transfer factor contains an RNA component that activates one or more of the toll like receptors. Indeed original work in the area of transfer factored seemed to demonstrate an RNAse III-sensitive activity in transfer factor [136].

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