37 patients with PDAC received ex vivo-expanded T cells that had been stimulated by DCs presenting peptides from 5 known TAAs. Tested polyclonal T cell products specifically responded to TAAs, comprised newly detected TCR clonotypes, and had memory phenotypes. Treatment was generally safe, and disease control rates were 84.6% and 25.0% in patients who did or did not, respectively, respond to first-line chemotherapy. Infused T cells persisted out to 1 year, and the frequency of TAA-specific T cells was higher in responders than in non-responders. Antigen spreading, polyfunctionality, and tumor infiltration were observed. 2 patients with resectable disease were relapse-free >5 years.
Contributed by Alex Najibi
ABSTRACT: T cell therapy has proven challenging for pancreatic ductal adenocarcinoma (PDAC), partly due to heterogeneous expression of tumor-associated antigens (TAAs). To address tumor heterogeneity and mitigate immune evasion, an ex vivo expanded, polyclonal, T helper 1 cell-polarized T cell product targeting five TAAs-PRAME, SSX2, MAGEA4, Survivin and NY-ESO-1-was developed. These antigens were chosen based on their tumor specificity, oncogenicity, immunogenicity and level of expression. In a phase 1/2 trial, this autologous nonengineered T cell product was administered (1 × 107 cells m-2 per infusion) monthly to patients with advanced PDAC responding (arm A, n = 13) or refractory (arm B, n = 12) to first-line chemotherapy or with resectable disease (arm C, n = 12). Primary endpoints were safety and feasibility of completing six infusions, whereas exploratory efficacy endpoints included persistence and evaluating the relationship between clinical benefit and the expansion of the infused effector T cells, as well as the induction of de novo immune responses. Of 56 participants procured, 37 were infused, with only 1 treatment-related serious adverse event. Disease control rates in arms A and B were 84.6% (95% confidence interval: 54.6-98.1%) and 25% (95% confidence interval: 5.5-57.2%), respectively. In arm C, two of nine resected participants remained disease free after 66 months of follow-up. The infused cells persisted up to 12 months posttreatment and elevated levels of tumor-directed T cells were detected during dosing (P = 0.027) and follow-up in responders compared to nonresponders. Clinical outcomes correlated with peripheral expansion of functional TAA-targeted T cell clones and treatment-emergent antigen spreading. Thus, further investigation of this approach, either as a single agent or combined with other complementary modalities, is warranted (ClinicalTrials.gov identifier: NCT03192462 ).
Author Info: (1) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, U
Author Info: (1) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. blmusher@bcm.edu. (2) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (3) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (4) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (5) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (6) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (7) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (8) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (9) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (10) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (11) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (12) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (13) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (14) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (15) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (16) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (17) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (18) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (19) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (20) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. (21) Center for Cell and Gene Therapy, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Texas Children's Hospital and Houston Methodist Hospital, Houston, TX, USA. aleen@bcm.edu.
