PD-1 Programmed Death for Cancer Cells “More, Please!” Dr. Wolchok

If anyone can find a cancer event exciting, it is the ASCO annual meeting, at which thousands of oncologists present their studies and learn from one another.  In the kidney cancer world, the “buzz” has been about “programmed death”–for the cancer cells, which we all prefer over that of our healthy cells.


This is a transcribed lecture, fairly short, to explain the immune therapies that may add to those weapons against RCC.  Dr. Wolchok clarifies how this happens, with the agents interfering with the “Shields Up!” commands that protect the cell from what should be their programmed deaths.  With appreciation to all researchers.

Peggy–Nine years of life free of cancer, thanks to the original immune therapy, HD IL2



ASCO Daily News June 6, 2013

Dr. Jedd D. Wolchok, MD PhD of Sloan Kettering Memorial Cancer Center

PD1 Pathway and Activity of Nivolumab

 http://chicago2013.asco.org/dr-jedd-d-wolchok-pd1-pathway-activity-novel-agent-nivolumab-potential-predicative-target  (Transibed interview with above link.  Easier to read and review, fans say!)

 We now recognize that there are several pathways that constrain T Cells and the immune system from achieving a state of full and persistent activation.

One of those pathways is called the CTLA4 pathway and there was a medicine approved call Ipilumimab last year, that blocks CTLA4 for treatment of melanoma. There is another pathway, the PD 1 pathway which usually constrains the immune system in a different way.  And PD 1 is also present on T cells in the immune system and it binds to a family of ligands, one of which is known as PD-L1 or PDL ligand 1.

In the ever-expanding a list of ways in which cancers try to evade the immune system, cancers have learned to express this PDL-1 ligand on their surface.  By doing so, they actually cause the death of T cells that come close enough to them or PDL-1 to bind to PD-1 on the T cell surface. This ability of cancer cells to express PD L1 on their surface allows them to defend themselves against T cells that the body is trying to educate to see the cancer and to defend itself.

So the PD-1 pathway is active across multiple disease sites. Some of the earliest work done with anti-bodies that block the PD -1 pathway used an anti-body called Nivolumab. Nivolumab was used in a phase 1 clinical trial that was presented at ASCO last year, and additional data will be presented this year.

The data last year showed that the antibody Nivolumab blocks PD -1, and that it can cause regressions in melanoma, in kidney cancer and importantly, really, non-small cell lung cancer. It is not traditionally recognized that as a cancer amenable to immune intervention. But when you people talk about cancers that responsive to immunotherapy, melanoma and renal cell carcinoma come to mind.

Now I think with the data generated first with Nivolumab and now with another PD-1 blocking antibody called Lambrolizumab(MK-3475), these anti-bodies which block the PD -1 pathway are demonstrating activity outside the “usual suspects”, melanoma and kidney cancer.

This ability to affect multiple different cancer types is important, as it shows that immunotherapy is not a treatment for one particular kind of cancer,.  It is a treatment that primarily targets the patient, Then it is the patient’s immune system that goes out and treats the cancer.

One of the most important characteristics of immunotherapy is its ability to induce durable and certainly there are many different types of anticancer medications which can cause a tumor to reduce in size, but the challenge has been and continues to be, how to get disease to regress and stay regressed.  Tumors, because of their genetic instability, can find pathways to become resistant to these interventions such as chemotherapy or targeted pathway inhibitions.

Immunotherapy really falls into a different category. Again, it is not targeting the tumor itself. It is targeting the patient’s immune system. It is causing the patient’s immune system to respond to certain parts of the tumor cells that the immune system finds interesting and then to control.

We know that the immune system has the ability to remember, through to a population of cells called memory cells.  Because the immune system is really a dynamic organ that cannot only sculpt itself around changes in the cancer, but also can remember what it has been exposed to in the past, we believe that durability is in fact a hallmark of response to immunotherapy. The first medicine to show us this in a meaningful way was a drug called interleukin two which was really actually developed now over 25 years ago and has led to the cure of some patients with melanoma and kidney cancer. That medicine is a hormone that causes the growth and differentiation of T-cells and patients who have a complete response to IL-2 and remain in complete response for at least two years don’t ever seem to recur with 10 or more years of follow-up.

We definitely need to learn more about the PD-1 pathway we specifically need to know whether it’s absolutely required for a tumor cell to express PDL-1 that on that surface to benefit from PD-1 or PD L-1blockade. It would be ideal, in fact, if a predictive biomarker that could identify the precise patient population who would benefit from that intervention. However, I think that is not going to be a simple as predictive biomarkers been for some of the targeted therapies, where it is mutation-present or –absent.  Here PDL-1 is not just important when it was expressed on the tumors, but PDL-1 plays a role by its presence on antigen-presenting cells. So, in its normal physiologic role, the PD -1 pathway actually involves interactions between T cells and antigen presenting cells and by blocking cells–even if the cells doesn’t express PDL-1–one could imagine that a patient could benefit, perhaps not as likely as if the tumor expressed PD L1.

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