San Francisco, CA USA (UroToday.com) Dr. Sharma presented the state of predictive biomarkers in today’s Immunotherapy for Urothelial Carcinoma session at the 2016 GU ASCO meeting. She began by discussing the rationale for developing immunotherapy as a treatment for advanced disease, stating that tumor antigens can be recognized by T-cells, tumor infiltrating lymphocytes are associated with a good prognosis, and that BCG has been a long-standing successful treatment modality for a subset of patients with superficial bladder cancer. Characterization of anti-CTLA-4 has opened a new field called immune checkpoint therapy.
One important consideration in the administration of immunotherapy is the selection of which patients will respond. Mutational load may be predictive, as tumor types with increased somatic mutations have demonstrated better response rates. Those with lower mutational loads still respond, but may depend on combination therapy. PD-L1 expression has been used as a biomarker for response, however, data by Powles (ASCO 2014) suggests that this may not be sufficient. Rationale for this requires a review of basic immunotherapy. Interaction of the T-cell receptor with tumor cells (signal 1) is not adequate to activate a T-cell response alone. Positive co-stimulation is needed as well, yet it is important to realize that attenuation is automatically activated along with proliferation (i.e. programming the “on” switch also yields an “off” signal). Once activated, CTLA-4 and PD-L1 emerge at the cell surface, and at this point, IFN-gamma is produced which increases PD-L1 expression. Biopsy at this time point would show PD-L1 positive tumor cells, while biopsy at the earlier point of co-stimulation may show PD-L1 negative tumor cells. Thus, the immune response is dynamic; PD-L1 expression at a single time point may not reflect an evolving immune response in the blood or tumor microenvironment.
Further evidence of this was presented by Powderly and colleagues, who identified the adaptive regulation of PD-L1 expression where PD-L1 negative cells became PD-L1 positive. The increase in concentration of CD8 T cells after treatment suggested that perhaps additional biomarkers, such as quantification of T-cell subsets, may provide better prognostic markers for clinical response. Sharma et al performed a comparative study of low vs. high concentration of CD8 cells, and found that extent of intra-tumoral CD8 tumor infiltrating lymphocytes is an important prognostic indicator in advanced urothelial cancer.
Dr. Sharma then discussed the relationship between cancer immunotherapy trials and laboratory investigation. While hypothesis testing is most efficient when one variable is analyzed at a time, hypothesis generation is more realistic in clinical settings through a discovery-driven approach. One example of a hypothesis generating pre-surgical clinical trial involved the use of anti-CTLA-4 in patients with localized bladder cancer who were scheduled for cystectomy. Blood was drawn pre-therapy followed by the administration of antibody. Blood was drawn again at week 3 and prior to surgery at week 7. RNA and TIL expression were assessed, and immunofluorescence and immunohistochemistry were performed at tissue procurement. Post-therapy, it was demonstrated that T-cells (CD3, CD4, CD8, Granzyme, and CD20) infiltrated into bladder tumor tissue. Immunofluorescence highlighted the integration of multiple immune markers. This generated the hypothesis that ICOS/ICOSL pathway is necessary for effective anti-tumor immune response in the setting of anti-CTLA-4 therapy. In a separate study, Fu, He, and Sharma showed that in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 significantly decline, thus inhibiting tumor rejection. A second hypothesis generated was that the ICOS/ICOSL pathway can be targeted and developed as a combination therapy strategy with anti-CTLA-4 or other immunotherapies to improve anti-tumor responses. Fan et al supported this hypothesis in a prostate cancer and melanoma mouse model, where concomitant CTLA-4 blockade and ICOS engagement with vaccines enhanced antitumor response.
Dr. Sharma concluded that immunotherapy elicits enhanced immune responses against tumors and provides durable responses. Immune responses are dynamic and evolve over time, thus expression of a single biomarker to select patients for treatment may not be appropriate. Longitudinal evaluation of tumor tissues should occur throughout treatment to define adaptive pathways that need to be targeted. Finally, tissue-based or pre-surgical clinical trials provide a platform to study evolving immune responses in the tumor microenvironment.
Presented By:
Padmanee Sharma, MD, PhD
The University of Texas MD Anderson Cancer Center
Reported By:
Nikhil Waingankar, MD at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Fox Chase Cancer Center, Philadelphia, PA