Is timing everything?
Unlike targeted therapies, there tends to be general agreement that it is unlikely that a single predictive biomarker in tumor biopsies will be found for determining response to immunotherapies. This is also holding true for the serological testing being performed for immuno-oncology predictive signatures using exosomes, serum proteins or ctDNA. Most investigators are searching beyond PD-L1 as the relative value and robustness of this biomarker continues to be evaluated.
At the recent ASCO-SITC Clinical Immuno-Oncology Symposium in Orlando, Dr. Jennifer Wargo (MD Anderson) presented intriguing data on the significance of looking for predictive biomarkers in melanoma. In this particular cohort, patients with metastatic melanoma were initially treated with a CTLA-4 inhibitor and then non-responders were treated with PD-1 inhibitor (full details found in Chen et al. 2016 Cancer Discovery). Tumor biopsies were collected at multiple time points during treatment including pre-treatment, on-treatment, and then progression as well. Wargo showed that immune signatures in pre-treatment tumor biopsies largely failed to predict response to checkpoint inhibitors, yet the signatures in on-treatment biopsies were highly predictive. This trend was shown both with a 12-marker immunohistochemistry panel as well as with gene expression profiling using a 795-gene panel (Nanostring). Wargo stated, ”We may have acceptable predictive biomarkers at present, but we may be simply looking at the wrong time point.” She urged that rather than putting an emphasis only on pre-treatment biomarkers for checkpoint therapy, we also should be investigating the adaptive immune signatures in early on-treatment samples as well.
Does this really mean the search for predictive biomarkers is over? These initial treatment time points may hold valuable clues to signatures of likelihood in patient response and should be incorporated into clinical trial study designs for further investigation. Yet, understanding whether or not a patient will respond to a treatment before actually initiating the therapy is still of high importance as to spare patients of ineffective drugs or treatment adverse events. As further discussed in Chen et al, perhaps this approach could be quite useful for clinical applications, ”…at least until better predictive markers in pre-treatment tissue and blood samples may be identified.”
Time is of the essence
One of the captivating plenary sessions at this year’s AACR meeting in Washington D.C. was a presentation by leading cancer researcher, Dr. Bert Vogelstein from Johns Hopkins University. Vogelstein’s talk promoted the value of early detection in cancer as key to lowering death rates. He provocatively probed the audience, “How do we achieve the next revolution in cancer?” He argued that the answer is attainable by using both new therapies and new modes for prevention. He humorously referred to the expert ability of cancer researchers to cure mice of cancer, but not humans. Why is this? It may be simple mathematics, the immense number of cancerous cells in human compared to murine disease studied in a controlled environment. But he urged that earlier detection of human tumors could make these tumors seem more like those of a mouse. Vogelstein shared promising statistics demonstrating that small burden of disease can be cured with chemotherapy treatment. For example, a provoking number of 94% of all Stage I cancers can be effectively cured using conventional chemotherapy.
Window of opportunity
Further, Dr. Vogelstein stated that “Prevention is as good, if not better than current therapies.” The powerful, innovative tools of cfDNA and ctDNA for early cancer detection are gaining traction as methods to assist in early diagnosis, as well as to monitor patient response. He implied that pharma companies should be investing in better technologies for early cancer detection/prevention due to the evidence that their drugs will be more effective in patients with minimum residual disease. As expected, the annual AACR meeting provided attendees with a variety of elegant talks from acquired resistance mechanisms, new insights into immune checkpoint blockade, to the latest results on adoptive cell therapies. There was a sense of excitement and energy as researchers continue to work to better characterize both the tumor and the complex microenvironment. Cancer researchers are truly “seizing the moment” as they look to transform the way we treat and detect cancer in the hopes that this disease will be managed as a chronic condition as opposed to a terminal one.