San Francisco, CA USA (UroToday.com) Dr. Gordon Freeman delivered today’s renal cancer keynote lecture on the science behind immune checkpoint inhibitors. While immunology has offered hope for curing cancer for the past century, the new strategy of checkpoint blockade has quickly gained momentum. Checkpoint blockade requires two signals: the T-receptor provides specificity to the immune response, and co-stimulatory signals then activate or deactivate the immune response.
In the PD-1 pathway, PD-L1 and PD-L2 are ligands for PD-1. Their association leads to phosphorylation of the cytoplasmic domain, leading to activation of proximal signaling kinases. This ultimately leads to reduced TCR signaling, less cytokine production, reduced target cell lysis, and altered lymphocyte motility; the total effect is deactivation of the T-cell. The purpose of negative signaling such as PD-1 is to tune down the immune response after elimination of disease, prevent an excessively strong immune response, and to maintain immune tolerance. PD-1 and PD-L1 blockade, then, stimulates anti-tumor immune response. As for location of checkpoint blockade, CTLA-4 functions in the lymph nodes while PD-1 works in the tumor, T-cell, APCs, and stromal cells.
A number of investigators have attempted to directly stimulate the immune response to cure cancer. This doesn’t work because once gamma-IFN is upregulated, PD-L1 is induced and turns off immune response. In effect, stepping on the gas also results in pumping the brakes.
With the relatively recent increase in immunotherapy utilization, 5 PD-L1 monoclonal antibodies have become available. To ensure the right patient is receiving the appropriate treatment, a number of studies have examined predictive markers for clinical response. These markers, however, are limited by the discordance in expression at various tumor sites, as well as the discordance in expression at various time points. Callea and colleagues have found 21% discordance between PD-L1 on the primary tumor and metastatic sites in ccRCC. If you stick a needle into a tumor, you may have sampling error and miss PD-L1 expression altogether, and thus it is recommended that the Pathologist should select high-grade areas specifically.
PD-L1 expression has been studied as a predictive marker for survival. Choueri and associates found that in a series of 101 non-clear cell RCC patients, PD-L1 expression was seen in 11%, and was associated with higher stage, grade, and poorer OS. A phase 3 study of nivolumab and everolimus (Motzer et al) confirmed that increased PD-L1 expression was associated with poorer survival, and that PD-L1 expression was not associated with PD-1 treatment benefit.
Other predictive markers to guide treatment have included B7 markers, butyrophilin family, VISTA, ICOS/ICOSL, and HHLA2. CD8 and CD14 are reflective of T-cell infiltration, and the high concentration of infiltrating lymphocytes suggests that kidney cancer is ripe for immunotherapy. The search for a target also requires an understanding of what the immune system “sees“ when it tries to attack the tumor. If immune system identifies a neoantigen, it will try to kill the tumor. In fact, many early tumors are eliminated before they become a “medical problem.” Those that grow have learned to evade immune response, and they do so via expression of PDL1, IDO, TGF-b, IL10, loss of MHC and others. Therefore, we need rapidly evolving treatment strategies in order to attack these potential targets.
Understanding immunology and genetics has led to the identification of groups that respond well to PD-1/PD-L1 therapy. These include highly mutated tumors, those with genetically amplified PD-L1 and PD-L2 (eg. Hodgkin’s), and those with viral antigens (eg. HPV, head and neck tumors, Merkel). T-cells need PD-1 blockade to attack the tumors because theoretically, T-cells have tried and failed, and are thus “exhausted.” Support for this theory comes from data from Barber and colleagues, who showed that PD-1 is upregulated in both acute and chronic immune responses. However, in an acute response, once an infection is cleared, PD-1 decreases, while chronic responses maintain PD-1 expression beyond infection clearance. These cells, now considered “exhausted,” are revived by PD-1 blockade. T-cell exhaustion has origins beyond PD1 though; exhausted tumor infiltrating lymphcytes express multiple immuno-inhibitory receptors, all of which are potential targets for tumor immunotherapy.
The future of immunotherapy is combination blockade. This includes PD blockade with other immunoinhibitors, immunostimulators, kinase inhibitors, cancer vaccines, oncolytic viruses, and many others. Questions that remain include identifying those that will be responders, mechanisms of failed response, and mechanisms of secondary failure to response.
Dr. Freeman concluded that it’s a wonderful time to be an oncologist or researcher. PD-1 works on a wide range of tumors with moderate percentage of responders and a good safety profile. With this success, human creativity has been unleashed.
Presented By:
Dr. Gordon J. Freeman, PhD
Dana-Farber Cancer Institute
Reported By:
Nikhil Waingankar, MD, at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Fox Chase Cancer Center, Philadelphia, PA