The New York Academy of Sciences held “Frontiers in Cancer Immunotherapy 2020” as an online symposium May 11–12, 2020.
Several presentations covered areas where focused ultrasound combined with immunotherapies could improve therapeutic outcome. It is important to note that these are potential avenues where focused ultrasound could play a role in the future. These included:
- If focused ultrasound can enhance the therapeutic effect of an immunotherapy, the required dose and any associated toxicities would be decreased, which would lead to novel immunotherapy combinations.
- Focused ultrasound could be used for local delivery of CAR-T cells to treat regional disease, particularly in the brain and for solid tumors.
- Focused ultrasound combination therapy for prostate cancer could improve T-cell infiltration in the prostate tumor microenvironment.
Additional information for each of these areas is detailed below:
Immunotherapy Combinations: Despite the cancer treatment revolution introduced by immunotherapies, there are still a small fraction of patients that respond to monotherapy (e.g., 20% of overall survival at 10 years for metastatic melanoma). Combining immunotherapies, such as anti-PD1 or anti-CTLA4, can improve this response. As of today, the overall survival in patients with metastatic melanoma treated with this combination is close to 50%, but a limiting factor is the increased toxicity.
Immune-related Toxicities: Millions of patients are treated with immuno-oncology (IO) drugs, notably immune checkpoint inhibitors (e.g., anti-PD1 or anti-CTLA4) that are used in adjuvant setting after resection of tumors, to prevent recurrences, in patients roughly without gross pathology. It is important to understand that IO drugs have associated toxicities, including colitis (very common) or heart toxicity (very rare but associated with high risk of mortality), and these toxicities are major barriers to producing more effective combinations. Work in progress includes improving our understanding of immune-related adverse events to allow for better management, defining more effective management strategies, and understanding the relationship between autoimmune toxicity and tumor response.
Progress on T-cell therapies: Currently available and in-development technologies can now produce patient-specific T-cells within 2 weeks. These therapies have been validated for blood cancer (e.g., lymphoma). Important barriers that must be overcome to improve outcomes include resistance and impaired trafficking, especially to solid tumors. These antigen-specific T-cells can theoretically be programmed to target multiple antigens of the patients’ tumors, in order to reduce evasion mechanisms of antigen loss. Optimal engineering strategies remain to be elucidated. Novel high throughout sequencing technologies (surfaceome profiling) will allow more rapid and in-depth analysis of tumors to identify candidate antigens. Preclinical brain tumor studies (a model for pediatric tumors) have shown that intracranial delivery of CAR-T cells is 10 times more potent than intravenous delivery, and several clinical trials using this approach are ongoing. Combination strategies, such as combination with checkpoint inhibitors, are also currently under study to improve T-cell therapies. A vision for the future of the approach would be to use T-cell therapies in a second phase of treatment after the disease burden has been decreased by chemotherapy, immune checkpoint inhibitors, or surgery to cure the minimal residual disease and achieve remission.
Treatment of Metastatic Prostate Cancer: Studies are ongoing to develop immunotherapy combinations to treat metastatic prostate cancer and overcome the immunosuppressive prostate tumor microenvironment. There are currently no approved checkpoint inhibitor therapies for the treatment of prostate cancer. Studies that have been performed with a PD1 or CTLA-4 alone did not demonstrate improved overall survival, although some patients showed improved progression-free survival. In an attempt to identify patients with castration-resistant prostate cancer who would respond to ipilimumab therapy, it was observed that immunological correlates associated with effector T-cell response were present in patients who benefited from immune checkpoint blockade. Ipilimumab was shown to enhance a systemic, antigen-specific T cells response. To improve the response to a CTLA-4 in these prostate cancer patients, a clinical trial investigated the combination of a-PD-L-1 with a-CTLA-4 and showed that the combination may improve the response in a subset of patients, maybe those with a relatively high tumor mutational burden To further improve the response, a clinical trial has now been designed that combines immune checkpoint therapies, a-PD-L-1 and a-CTLA-4, with radiation therapy and neoantigen vaccine. New combinations will be needed to provide clinical benefit for a greater number of patients.
Thank you to Frédéric Padilla, PhD, the Foundation’s Director of Applied Physics Research, for attending the virtual meeting and submitting this report.