Immune checkpoint blockade in renal cell carcinoma

Published on March 31, 2016   58 min

Other Talks in the Series: Immunotherapy of Cancer

Other Talks in the Series: The Kidney in Health and Disease

Hello, my name is David McDermott. And I'm a medical oncologist at Beth Israel Deaconess Medical Center in Boston, Massachusetts. And I'm leader of the kidney cancer program at the Dana Farber Harvard Cancer Center as well as an associate professor of medicine at Harvard Medical School. And I'm here to talk to you today about immune checkpoint blockade in renal cell carcinoma.
During my career as a medical oncologist, there have been two waves of interest in immune therapy for solid tumors. I became a physician during the first wave. I graduated from medical school in 1992, when the use of cytokine-based immunotherapy was just reaching its peak, with the approval, in the United States, of high dose interleukin 2. Right after graduating from medical school, I began to focus on medical oncology. I was interested in learning more about the immune response to cancer and began doing research in this area. Needless to say, over the next 10 or 15 years, the interest in solid tumor immunotherapy began to decline dramatically, maybe sort of coinciding with my career in medical research. There was a significant rise in the application of molecularly targeted therapies, which began to replace these agents, particularly in kidney cancer, where many of the VEGF targeted agents proved superior to the old cytokine-based immunotherapies. However, in the last five to six years, there's been a dramatic increase in interest in the field of immunotherapy not just for kidney cancer but for other solid tumors. And these forms of immunotherapy have included vaccines, recombinant t-cell receptors, bi-specific T-cell engagers, but, most interestingly, these so-called checkpoint inhibitors, which have recently become approved in metastatic kidney cancer.
Why is this renewed interest possible? Well, we have a much better sense of how the immune system controls cancer or, more importantly, how tumors use complex and sometimes overlapping mechanisms to suppress the immune response to cancer. They do this by many ways. On this slide, we see that tumors can inhibit tumor antigen presentation, through the down regulation of MHC class I. They can suppress immunosuppressive factors in the tumor microenvironment, like TGF-beta. They can also recruit immunosuppressive cell types into the microenvironment, for example, T-regulatory cells, producing immunosuppression, locally. But probably most importantly, they can express these so-called checkpoint inhibitors, which work to inhibit immune cells that have actually detected the tumor, found their way into the tumor microenvironment, and would otherwise kill the tumor if it wasn't for their expression, on the tumor or on immune cells near the tumor. These checkpoint inhibitors sort of act like barbed wire, deleting T-cells that have found their way all the way to the tumor but are prevented from killing it.
Much of the work in this area is done by my colleagues at Harvard, Gordon Freeman and Arlene Sharpe, who've been pivotal in discovering many of these checkpoint inhibitors and their function in cancer. Here's an example of one of their initial discoveries. They were critical in the involvement of discovering both PD-L1 and PD-L2 and their roles in inhibiting T-cell activation. This is one of their papers showing that you could find PD-L1 on breast cancer cell lines, and this would inhibit the immune response to these cell lines, a very important discovery in this field.
So here's sort of a simplified way of how we think anti-PD-1 blocks T-cell suppression. So you see here, on the left side of the slide, in a typical situation, it's the antigen presenting cell that's creating sort of a co-stimulatory response to turn on a T-cell. But this antigen presenting cell can also shut off an activated T-cell by expressing PD-L1 on its surface. When PD-L1 becomes engaged with its receptor on T-cells, so-called PD-1 or Programmed Death 1, this can lead to the deactivation of the T-cell. This deactivation process can be sort of co-opted by a tumor, meaning normally it's antigen presenting cell is producing PD-L1 and expressing it on their surface. Here, you see how tumors can use the same machinery. They can express PD-L1 and deactivate T-cells that otherwise might contain or kill the tumor. This process can be reversed by blocking antibodies that either bind to PD-1 or PD-L1 on the tumor or in the tumor microenvironment. This reverses that T-cell suppression and leads to activation of the T-cell. Importantly, activation of the T-cells that are already in the tumor microenvironment, leading to the cytokine production and lysis tumor cell death. The fact that this interaction is going on within the tumor probably also explains the clinical activity of these drugs, because these are activating T-cells that already can recognize the tumor. And in some ways, it explains the relatively favorable toxicity profile. Because much of the action here, that's being stimulated, is happening locally, at the site of the tumor, and not globally throughout the body.

Immune checkpoint blockade in renal cell carcinoma

Embed in course/own notes