San Francisco, CA USA (UroToday.com) Dr. James Gulley presented the medical oncologist’s perspective of checkpoint blockade in today’s immunotherapy session at the 2016 GU ASCO conference. He began by discussing history of BCG, highlighting its limited efficacy (up to 50% have recurrence after the induction cycle, and only 25-45% of these benefit from a second induction cycle) and its high toxicity profile (63% have side effects). The recent BCG shortage adds to its limitations and highlights the need for alternative treatment strategies.
Immunotherapy remains a solution simply because neoantigens expressed in the tumor are not expressed in other tissue. These antigens are taken up by dendritic cells, travels back to lymph nodes, interact with T-cells, and activate them. T-cells then travel back to the tumor and kill tumor cells. Upon activation, gamma interferon is produced and up-regulates PD-L1, which binds to PD1 on the T-cell and impairs its ability to kill tumor cells. Antibody to PD1 blocks this interaction and allows the T-cell to continue killing tumor cells.
An important consideration in using immunotherapy is determining which patients will benefit. Mutational load may be prognostic of the response to immunotherapy, and those tumor types with increased somatic mutations have a higher concentration of target neoantigens. These tumor types can be considered “T-cell inflamed” while those with fewer mutations can be considered “T-cell poor.” T-cell inflamed tumors tend to exhibit a greater response to checkpoint inhibitor strategies.
Long term follow-up has shown that patients who survive up to 36 months will do well up to 10 years; Schadendorf et al showed that 20% of patients have long term disease control. While the durability of response is impressive, it is important to identify strategies that produce the same response in a greater proportion of patients. Combination therapy, also termed “immunogenic intensification” is a potential solution that can improve this. Larkin and associates studied this in a stage III RCT of unresectable melanoma patients. Those receiving Nivolumab had a mean change of 34.5% decrease in tumor volume, those receiving Ipilimumab had a mean decrease of 5.9%, and those receiving combination therapy had a mean decrease of 51.9%. The greater response came at a significant cost, as 55% in the combination group experienced grade 3 or 4 adverse events, vs. 16.3% and 27.3% in the Nivolumab and Ipilimumab groups, respectively.
An alternative strategy may be to attempt to increase the ratio of T-poor: T-inflamed infiltrating lymphocytes. Unpublished data from NCI showed an increase in T-inflamed cells (increased PD-L1 expression) after administration of a vaccine, compared to the response after administration of saline. Other agents that cause T-cell inflamed tumors include BCG, CTLA-4 blockade, intratumoral cytokinds (NHS-IL-12), NK cells (ACT or cytokines), TKI, and radiation. Agents that inhibit T-cell activation include TGF-B, IDO, IL-10, and VEGF.
Dr. Gulley concluded that while BCG is the current standard of care, it remains suboptimal. Immune checkpoint inhibition has good activity in advanced disease and is well-tolerated; a logical next step is to use it in non-muscle invasive bladder cancer. Finally, combination therapy may lead to better outcomes than monotherapy.
Presented By:
James L. Gulley, MD, PhD
National Cancer Institute at the National Institutes of Health
Reported By:
Nikhil Waingankar, MD at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Fox Chase Cancer Center, Philadelphia, PA