I attended the annual American Association for Cancer Research (AACR) meeting in Chicago this month where there was great excitement around recent developments in immunotherapy. From several presentations and networking events four big takeaways stood out to me:
One: Checkpoint inhibitor immunotherapy is rapidly becoming a standard of care in many oncology indications as the recent positive data showed significant recurrence-free survival in stage III melanoma in adjuvant setting. There are numerous combination therapies being explored, but only the combination of chemotherapy with Keytruda has changed standard of care in frontline NSCLC in PDL-1 low tumors. It appears to be a class effect as Ketruda and more recently Tecentriq have shown this benefit in frontline NSCLC.
Two: A notable body of work shows the immunosuppressive tumor environment plays a critical role in determining response to checkpoint therapy. Besides mutations in gamma-interferon receptor, mutations in JAK-1/2 or beta-2 macroglobulin leads to non-responsiveness to checkpoint treatment. A significant number of targets on MDSC and macrophages are being examined that play a part in immunosuppression. It will be another one or more years before we see early clinical data from these approaches.
Three: Antibodies to CSF-1R have demonstrated positive anti-tumor preclinical activity but clinical data is currently inconclusive. The combination of intra-tumor TLR9 agonist plus anti-CTLA4 demonstrated early positive data in patients progressing from PD-1/PDL-1 therapy. Interestingly, a CD11 agonist antibody showed re-polarization of tumor-associated macrophages to non-suppressive phenotype and decrease in tumor growth in preclinical studies. There were no clear answers why IDO inhibitor did not show positive data in combination with Keytruda in Phase 3 study. Should we lower the expectations on this class of molecules? I am not yet ready to give up on this class based on one product yet.
Four: There is a significant, ongoing bio-informatics-based effort to identify tumor mutations/neoantigens. These neoantigens are being tested as peptide-based vaccines or delivered through viral vectors either systemically or directly in the tumor. Many of these approaches show generation of antigen-specific T cell responses but limited clinical efficacy in the early trials. Many creative efforts are ongoing to better identify actionable mutations and are also being tested in combination with anti-PD-1. Will personalization lead to better products? I am bullish on this based on recent results but the approach requires diverse multifunctional expertise to pull it off.