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发表于 2013-11-17 02:35:49
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来自： 美国
本帖最后由 jaydad 于 2013-11-17 19:02 编辑
Note from my quest for immunotherapy trial -
This week, I received a call from Dr David Gerber's office in UT Southwest Medical School to inform me that the last arm of the BMS anti-PD-1 (BMS936558 /Nivolumab) for previously treated squamous lung cancer, has been closed - I have non-squamous cancer anyway. So of all the PD-1 and PD-L1 based immunotherapy trials out there for lung cancer, I am truly lucked out. I hope they will either open new ones or get FDA approval soon.
In recently years, companies including Dendreaon and Bristol Squibb Meyer, have made long stride starting move cancer immunotherapies from lab to the mainstream of cancer therapy.
The approval of Dendreon’s prostate cancer vaccine Provenge (Sipuleucel-T) in 2010 was an important step forward in cancer treatment. But since the vaccine can only be made for individual patient, production time and cost can become problem. “The vaccine is made by removing some of a patient’s white blood cells and sending them to a lab, where they are activated by exposing them to a protein found on prostate cancer cells. The cells are then given back to the patient about 3 days later, in a process similar to a blood transfusion. This is done 3 times, with about 2 weeks in between each dose.”
A year later, BMS’ Ipilimumab aka Yervoy, a fully humanized anti CTLA-4 monoclonal antibody, was approved by the FDA to treat late-stage melanoma that has spread or cannot be removed by surgery. This approval was regarded as game-changer in cancer immunotherapy because it overcomes mass production issue that was hindering Provenge. Ipilimumab is also in trials for other cancer – prostate and lung cancers. In addition to BMS’ Ipilimumab, which is an IgG1 isotype, Medimmune is developing and testing tremelimumab which is an IgG2 isotype, currently in testing for melonoma, mosothelioma and liver cancer.
Ipilimumab works by turning off the inhibitory mechanism and allows Cytotoxic T lymphocytes to continue to destroy cancer cells. Cancer cells produce antigens, which the immune system can use to identify and destroy them. These antigens are recognized by dendritic cells, which present the antigens to CTLs in the lymph nodes. The CTLs can then recognize the cancer cells by those antigens and destroy them. However, dendritic cells also present the antigens to CTLs along with an inhibitory signal, which binds to a receptor, CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive. Ipilimumab blocks the CTLA-4 inhibitory signal, and allows the CTLs to destroy the cancer cells.
While it has only been shown to shrink tumors in less than 20 percent of patients, the patients who gain from it tend to live a long time because the immune system is adaptable and can keep up with mutations in the tumor. The longest recorded survival was 9.9 years. Still, ipilimumab treatment has been associated with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation. Most of the serious adverse effects are associated with the gastro-intestinal tract; they include stomach pain, bloating, constipation or diarrhea, but also fever, breathing or urinating problems. So though already in the market, it’s not yet, actually far from picture-perfect.
Another star candidate from BNS, Nivolumab, aka BMS-936558, works by attacking PD-1 instead of CTLA-4 on T cells. It’s an anti-PD-1 monoclonal antibody that has produced objective responses in approximately one in four to one in five patients with non–small-cell lung cancer, melanoma, or renal-cell cancer, while its adverse-event profile does not appear to be any worse than ipilimumab. For NSCLC, ORR was 17% (22/129). Merck’s heavy weight candidate, lambrolizumab, MK-3475, also an anti-PD-1 monoclonal antibody has also joined the race to market.
Nivolumab can be combined with ipilimumab and the combo has been shown to lead to deep tumor regression (CR+PR) in 40% patients who have advanced melanoma, a far higher rate than is seen with ipilimumab alone. The response is shown to be quicker when the combination is used versus a single drug. Including slow responses or stable diseases, 65% of patients had the melanoma controlled with this combination. Ninety percent of the responding patients continued to respond a year later. Results like this is indeed pushing melanoma towards a “curable” disease. BMS recently opened this study, NCT01928394, A Phase 1/2, Open-label Study of Nivolumab Monotherapy or Nivolumab Combined With Ipilimumab in Subjects With Advanced or Metastatic Solid Tumors. The website says it only includes SCLC – i think they mean NSCLC.
BMS has yet another candidate, anti-KIR monoclonal antibody, Lirilumab in development. KIR stands for killer cell immunoglobulin-like receptor, so it counts on NK (natural killer, innate immunity) cells instead of T cells (adaptive immunity). Study NCT01714739, A Phase I Study of an Anti-KIR Antibody in Combination With an Anti-PD1 Antibody in Patients With Advanced Solid Tumors (including NSCLC), is recruiting patients, but has no data yet.
Newer to the lines of lung cancer immunotherapy are anti-PD-L1 monoclonal antibodies. They are Medimmune’s anti-PD-L1 Medi4736, for melanoma, RCC, NSCLC and CRC; Roche / Genentech’s anti-PD-L1 antibody MPDL-3280A, for skin, lung and kidney cancer. PD-L1 is a surface antigen on tumor cells that is ligand for the PD-1 receptor on T cells. So my layman understanding is that attacking tumor cells must sound psychologically safer as compare to attacking immune system cells directly.
In truth, anti-PDL1 therapy was first tested in clinical trial by BMS, with BMS-936559, an IgG4 monoclonal antibody, which inhibits the binding of PD-L1 to both PD-1 and CD80 – NCT00729664 Multiple Ascending Dose (MDX1105-01) (Anti-PDL1). Treatment-related grade 3 or 4 toxic effects occurred in 9% of patients. Objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma (~17%), and 5 of 49 with non–small-cell lung cancer (~10%) – a bit low. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up. So my guess as why BMS does not pursue it further was because of its border-line % efficacy (at least in Lung CA), relative to their anti-PD-1 candidate, BMS-936558, aka nivolumab.
Roche/ Genentech’s anti-PD-L1 candidate MPDL3280A, a fully humanized monoclonal antibody, showed mild toxicity profile in phase 1 study, including fatigue (2%), dyspnea (shortness of breath; 0.7%), nausea (0.4%) and vomiting (0.4%), and no pneumonitis. No dose-limiting toxicities were identified in this trial.
With an overall response of 23% for 53 NSCLC patients, and especially when PD-L1 expression (>10% cancer cells positive for PD-L1 in IHC staining considered high) was factored in, the response rate goes up to 83%. Genentech is moving forward swiftly in Phase 2 study that prescreens participants for PD-L1 expression. The success story of Pfizer’s crizotinib has far-reaching influences on future cancer drug development. Genentech a few months ago opened a new study, NCT01846416, A Study Of MPDL3280A in Patients With PD-L1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer. We all know how effective taxotere is against NSCLC, so it is conceivable to see Genentech is also testing MPDL3280A vs taxotere, without requiring patient prescreening, NCT01903993, A Study of MPDL3280A Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Platinum Failure. Genentech says smokers respond better than never-smokers, but I think it is premature to conclude.
Medi4736 has not provided an update in recent conferences, but Medimmune has just created a new clinical study, A Phase 1 Study to Evaluate MEDI4736 in Combination With Tremelimumab, NCT01975831. This is in addition to another study evaluating MEDI4736 as a single agent therapy, NCT01693562. |
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