Programmed Death-1–My Death Wish for Cancer–and Clinical Trials

PD-1—Programmed Death and Clinical Trials

 Even doctors need to study this stuff! Doctors are offered online study modules, and recently the topic of “immunotherapies” was offered.  This module explains the PD-1 antibodies and related BMS-936558 clinical trials, which is of interest to kidney cancer patients.  Since I am not trained medically, so this is my perspective as a patient only. Perhaps this  will start a discussion with you and your doctor, andupdate you about immune therapies and PD-1 studies.  Your corrections and comments are requested.

May I remind readers that the body’s immune response is a series of signals and responses, organized so that normal cells can grow and infections can be controlled without an overreaction of the immune system. But the immune system is not perfectly equipped to handle the mutations that characterize cancer, so when these signals get interrupted, or are not received properly, cell development goes wrong.

The FDA recently approved ipilumumab, an anti-body which has benefit in fighting prostate cancer, as it blocks a molecule called CTLA-4.  That is one of severalimmune checkpoints, and is one of the “call and response” pairs that is active in cancer and chronic infectious diseases.  Another of these immune checkpoints is PD-1 (programmed death-1), which arises early in the process of T-cell (fighter cell) exhaustion.  It binds with a molecule called ligand (think ligature as to meaning), PD-L1.  This will appear on the surface of a tumor cell, and may be a measurable signal that the interaction of the PD-1 and its ligand, PD-L1 are suppressing the natural anti-tumor immune response.  This interference with the natural immune response permits the cancer cells to grow more easily. Thus the goal of the research will be to interrupt this binding.  Theoretically, that will make the ongoing immune response more effective.

This theory is being tested and contested, as there seems to be another response in melanoma. Since both kidney cancer and melanoma have some immunogenic qualities in common, what happens in melanoma research is of interest to RCC researchers.

Researchers have developed molecules that block the PD-1/PD-L1 interaction; one of these molecules is the BMS-936558 from Bristol Meyers Squibb which is also referred to as MDX-1106.  A phase I trial which tests safety and with increasing doses, showed benign toxicity. That led to an expansion of the trial of 300 patients, and still showed minimal toxicity.

There were objective tumor responses in patients with advanced melanoma (28%), non-small cell lung cancer (18%), and kidney cancer (27%).  Some patients had response of stable disease for six months, and others up to one year.

Of the RCC patients as a group were “heavily pretreated.”  Patients had previously received one or more treatments, with 47% having had three or more treatments.  Other trials corroborated this type of result, and act as proof of concept that blocking PD-1 can give clinical results without undue toxicity.

Another phase II trial of BMS-936558 is now complete and should be published soon.  It used the agent in second- and third-lines of treatment, after other treatments have failed.

With that and other data, a phase I trial combining the PD-1 blockade action with TKIs, such as Sutent (Sunitinib) and Votrient (Pazopanib) is underway.  There is also a bio-marker trial with the patients who responded to treatment, which includes both pretreatment and on-treatment biopsies for histologic and molecular analysis.

Reading that there would be analysis of markers in those responding patients compelled me to write this.  We are long overdue for research on the responding patients, which may determine who is likely to respond, and to prevent those non-responders from using ineffective drugs.  Apparently preliminary data from the large 300 patient group has shown that there were tumor responses ONLY in the patients who expressed PD-L1, and no responses in patients without this PD-L1.  Since this can be measured, this might prevent patients from taking treatment likely not to be beneficial, and to determine the optimum doses.

Another trial with a very similar name—different number—uses the antibody BMS-936559—note the NINE—and attempts to block PD-L1 directly.  While many cancer types were included in this study, it is noted again that patients with melanoma (17%), non-small cell lung cancer (NSCLC) (10%), renal cell (12%) and ovarian cancer (6%) had objective tumor response, as well as a range of stable responses at six months.

Most combination trials of have been with two TKIs, like Sutent and Pazopanib, which seems to offer little benefit, but with greater toxicity.  This new combination offers two different mechanisms of action, this may give greater results without the additional severe side effects.  We may also learn who is more likely to respond to any one of these drugs, which would be invaluable to the patient.

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