EM1510G "Cancer Immunotherapy: The End of the Beginning" (IM-GR100915)
Given the activity noted with both CTLA-4 or PD-1 blockade, clinical trials are now investigating combination checkpoint blockade. The most mature data with a combination of ipilimumab + nivolumab in melanoma showed a response rate of 40% across dose cohorts with >50% in some cohorts in the context of manageable toxicity. Such responses are generally durable, even when treatment was stopped early for toxicity. Unlike in studies of PD-1 blockade monotherapy, there was no significant difference in clinical activity based on tumor expression of PD-L1. Phase 2 and 3 trials of this combination are ongoing in melanoma with phase 1 programs in numerous other tumor types.
Attention is being paid to the reasons underlying the efficacy of checkpoint blockade in certain malignancies. One hypothesis has been that cancers having a high mutational load may be more amenable to immune modulation by virtue of the larger number of potential neo-epitopes present, fostering baseline immune recognition that can then be potentiated by checkpoint blockade. We have found that melanoma patients having long term clinical activity with ipilimumab have a significantly greater median number of non-synonymous passenger mutations, compared with patients who do not respond or those who have only short-term regression. The use of whole exome sequencing has allowed us to explore the additional hypothesis that the higher likelihood of response observed may not simply be explained by a higher quantity of mutations but rather that the individual immunologic quality of mutations is also important. Using a novel bioinformatics platform, we have found sub-strings of class I epitopes (tetrapeptides) shared by clinical responders and not found in the non-responders. Intriguingly, the vast majority of these favorable substrings are also found in known epitopes derived from proteins found in bacteria and viruses.
UT Southwestern faculty, fellows, residents and medical students, commnity physicians, nurse clinicians, physician assistants and nurses.
At the conclusion of this activity, the participant should be able to
- Understand the rationale for cancer immunotherapy.
- Identify agents currently active in various disease with respective toxicities
- Understand the rationale for combination therapies
Jedd Wolchok, M.D., Ph.D.
Lloyd J. Old / Virginia and Daniel K. Ludwig Chair in Clinical Investigation
Chief, Melanoma and Immunotherapeutics Service
Associate Director, Ludwig Center for Cancer Immunotherapy
Professor of Medicine, Weill Medical College of Cornell University
Memorial Sloan-Kettering Cancer Center, New York, NY
Pamela Hearn Isom Visiting Lecturer
- 1.00 AMA