NorthWest Biotherapeutics Inc (NWBO)

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Immunotherapeutic Niches, Competition and Collaboration. Part III: Immunomodulation — Anti-CTLA-4 MAb

Note: Anti-PD1, Anti-PDL1 and Regulatory T cell Depleting Reagents are also immunomodulators, and they will be discussed in parts IV and V of this series.


This five-part series covers DCVax and other immunotherapeutic approaches used in the fight against cancer. This subject matter is limited to most current major treatments recognized recently in the Journal of Neuro-Oncology, and I am including another group referred to as immunostimulants.

In all, there are 17 therapies that can be placed into four approaches which treat cancer. The four Immunotherapeutic Approaches herein are:

I. Vaccination
II. Cellular
III. Immunomodulation
IV. Immunostimulants


Part III addresses an immunomodulation approach that uses antibodies to artificially prolong a T cell immune response by temporarily blocking CTLA-4 molecules located on the surface of T cells. It is one form of checkpoint inhibition. This discussion is broken down into three subsections: Niche, Potential Competition with DCVax, and Potential Collaboration with DCVax.

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A. Ipilimumab — Brand Name, Yervoy, uses an immunomodulation therapeutic approach.

i. Potential Niche for Yervoy

Yervoy, made by Bristol-Meyers-Squibb, is a monoclonal antibody targeted to block CTLA-4 stimulation. CTLA-4 is a protein molecule found on the surface of CD4 T cells (Helper T cells), CD8 T cells (Cytotoxic/tumor killing T cells) and Regulatory T cells (T cells that end immune system responses). As described below, Yervoy’s method of action places it in a class of immunomudulators known as "checkpoint inhibitors.”

CTLA-4 molecules are upregulated to the surface of T cells when a prolonged immune response occurs. Normally, toward the end of any immune response, the same costimulatory molecules presented by Dendritic Cells to the T cell that would otherwise stimulate T cells to attack cancer cells, instead now bind to the more numerous upregulated CTLA-4 molecules on the T cells; thereby instructing them to instead stop their attack.

Yervoy antibodies turn off this braking capacity of T cells by binding/blocking upregulated CTLA-4 molecules for a period of time so that T cells can continue attacking tumor cells. In other words, “checkpoint inhibition,” a form of immunomodulation, occurs when Yervoy antibodies temporarily block T cell upregulated CTLA-4 molecules from binding with dendritic cell costimulatory molecules.

Yervoy also demonstrates a second method of action. In recent studies, it was proven that Yervoy also depletes Regulatory T cells in tumors and lymph nodes, thereby allowing an immune response to continue. Both mechanisms modulate the immune system, and for this reason, they are known as immunomodulators.

Unfortunately, Yervoy antibodies block t-cell braking capacity indiscriminately throughout the body for a period of time. This often results in the immune system attacking healthy human cells as well. According to the FDA, severe to fatal autoimmune reactions were seen in 12.9 percent of patients treated with Yervoy. When severe side effects occurred, Yervoy was halted and corticosteroid treatment was initiated. Not all patients responded to corticosteroid intervention. The prescribing information contains the following black box warning:

Yervoy can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system; however, the most common severe immune-mediated adverse reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of these immune-mediated reactions initially manifested during treatment; however, a minority occurred weeks to months after discontinuation of Yervoy.

Yervoy was studied in recurrent unresectable melanoma patients previously treated with surgery plus either chemotherapy or interleukin-2. Overall survival in patients receiving Yervoy was approximately 10 months versus 6.4 months in patients receiving a gp100 (a passive synthetic peptide vaccine using melanoma antigens). The overall response rate for Yervoy was approximately six to eleven percent. While the response rate was very low, a majority of those six to eleven percent of patients who did respond survived at least 2 more years. Approximately one percent achieved a complete durable response without further treatment.

In a second phase three trial, Yervoy was studied in previously untreated metastatic melanoma patients. Yervoy, plus the chemotherapeutic standard of care, only increased overall survival beyond the standard of care alone by 2.1 months. However, survival rates at one, two and three years were approximately double in the Yervoy + SOC patients versus those receiving SOC by itself: (47% (one year), 36% (two years) 29% (three years) versus 21%, 18%, 12%). Still, serious adverse events doubled when the combination therapy was used.

Regarding other possible indications, Yervoy appeared too toxic for use in lung cancer therapy, and it did not meet its primary endpoint in a trial for prostate cancer therapy.

Conclusion:

Yervoy is essentially a treatment for recurrent unresectable melanoma that is no longer responsive to first line chemotherapy. Yervoy is often extremely toxic, and consequently, this therapy must be monitored very closely. Yervoy therapy is priced at approximately $120,000 for a course of therapy. This cost does not include medical life saving intervention, hospitalizations and additional treatment courses for further recurrence.


ii. Potential Competition between DCVax and Yervoy.

Among other indications, NWBO’s DCVax-Direct phase I trial results will dictate whether they will pursue melanoma therapy in their upcoming phase II multi injection trial to treat solid tumor cancers or simply pursue label extension after DCVax-Direct is approved. DCVax-Direct safety will certainly be a major advantage, as this was already established in the phase I Direct trial. DCVax-Direct will be more cost effective than Yervoy, in that Yervoy often requires additional medical intervention and hospitalizations. Also, one course of treatment (four 90 minute infusions over 12 weeks) for Yervoy is priced at $120,000.00. If a patient taking Yervoy demonstrates recurrence, another 120,000.00 course of treatment is required; whereas, DCVax-Direct may be priced at or near $100,000.00; and one batch can potentially last upwards of three years.

iii. Potential Collaboration between DCVax and Yervoy.

Dr Kris Thielemans - Medical School of the VUB, Brussels, Belgium recently had some success in a 39 patient trial using Yervoy with a dendritic cell based vaccine to treat advanced melanoma. The response rate was approximately 20% when the combination was used. http://ecancer.org/conference/505-1st-immunotherapy-of-cancer-conference--itoc-1/video/2708/dendritic-cell-vaccination-combined-with-ctla4-blockade.php Only 4 tumor antigens were used in this dendritic therapy trial which likely allowed tumor variants to escape more readily. There were many serious side effects involving the combination consistent with those previously found during therapy with Yervoy. The overall median survival was 14 months, which was a four month improvement over historical therapy results with Yervoy + SOC.

Linda Powers recently voiced NWBO’s safety concerns regarding any conceivable cocktail therapies combining DCVax and checkpoint inhibitors. Yervoy is perhaps the most toxic checkpoint inhibitor on the market today, therefore NWBO is unlikely to pursue any potential collaboration in the foreseeable future.

Conclusion:

While Yervoy theoretically could be combined with the DCVax platform, Yervoy (and Tremelimumab, see below) present far too many adverse events with very low response rates. Consequently, no collaboration with DCVax seems likely in the foreseeable future.


B. Tremelimumab is also an immunomodulation therapeutic approach using Anti-CTLA-4 MAb.

After it failed to reach its primary endpoint in a phase III melanoma trial last year, it appears that this therapy will only be advanced, if at all, when used in combination with other treatments. Like Yervoy, Tremelimumab is very toxic with a low response rate, and it is unlikely it will be used with the DCVax platform in the foreseeable future.