The success of T-cell therapies for solid tumors has been limited, among others, by the scarcity of tumor-specific targets. To better understand how successful T-cell responses induced by immune checkpoint blockade (ICB) eliminate metastatic tumors, we conducted a longitudinal landscape analysis of the neoepitope-specific T cells during treatment in patients with melanoma with and without response to ICB. We characterized the target of the T-cell responses and their evolution over time in peripheral blood and tumor. In these studies, we showed that all patients presented neoantigen-specific T-cell responses that were tumor-reactive and targeted a limited number of immunodominant epitopes. Interestingly, in patients with clinical benefit from ICB, these responses were polyclonal, with multiple TCR clonotypes specific for the same mutations, and recurrently detected over time.
Alternatively, a promising therapeutic option for patients without response to ICB is adoptive T-cell therapy with T cells genetically modified to target shared antigens. We propose targeting the surface expression of TYRP1 to treat cutaneous and rare subtypes of melanoma. Using a fine-tuning engineering approach, we developed a highly-sensitive CAR-T cell therapy that detects the low amounts of TYRP1 localized on the cell surface. The TYRP1 CAR-T cell therapy presents robust antitumor activity without toxicity in murine and patient-derived cutaneous, acral, and uveal melanoma models. Based on this efficacy and safety profile, we are currently planning the phase I clinical trial.
Hosted by Ramon Alemany – Cancer Immunotherapy group
Cristina Puig-Saus, Ph.D. is an Assistant professor at the University of California, Los Angeles (UCLA). Dr. Puig-Saus is also a Senior Fellow from the Parker Institute for Cancer Immunotherapy (PICI) and a member of the Jonsson Comprehensive Cancer Center (JCCC) and the Broad Stem Cell Research Center (BSRCR). She graduated from the University of Barcelona, and after completing her Ph.D. work developing strategies to improve the design of oncolytic adenovirus, she joined Dr. Antoni Ribas’ team at UCLA as a postdoctoral fellow. During her postdoctoral training, she focused on developing new adoptive cell therapy strategies using hematopoietic stem cells. She led the preclinical effort that culminated in a clinical trial that opened at UCLA to co-administer stem cells and T cells genetically modified to express a NY-ESO TCR for the treatment of melanoma, multiple myeloma, and sarcoma.
Dr. Puig-Saus now leads her independent laboratory at UCLA focused on the design and clinical translation of novel TCR and CAR-engineered T cell therapies for cancer treatment. To this end, Dr. Puig-Saus’ team is developing multiple receptors and other engineering strategies to generate potent T cell-based cancer therapeutics. Her team is also studying the mechanisms behind the successful T-cell responses unleashed by immune checkpoint blockade in patients with response to therapy to mimic these successful T-cell responses into engineered therapies.