Adoptive T cell therapy of solid tumors: time to team up with immunogenic chemo/radiotherapy

2022 ◽  
Vol 74 ◽  
pp. 53-59
Arianna Pocaterra ◽  
Marco Catucci ◽  
Anna Mondino
2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3151-TPS3151
Bartosz Chmielowski ◽  
Samuel Ejadi ◽  
Roel Funke ◽  
Todd Stallings-Schmitt ◽  
Mitch Denker ◽  

TPS3151 Background: Neoepitopes (neoE) derived from private tumor-exclusive mutations represent compelling targets for personalized TCR-T cell therapy. An ultra-sensitive and high-throughput process was developed to capture tumor mutation-targeted CD8 T cells from patient blood. NeoTCRs cloned from the captured CD8 T cells, when engineered into fresh CD8 and CD4 T cells, effected killing of patients’ autologous tumor cells in vitro. These observations have been leveraged for the development of a fully personalized adoptive T cell therapy (NeoTCR-P1). A Phase 1 clinical trial testing NeoTCR-P1 in subjects with solid tumors is ongoing (NCT03970382). Methods: During the initial trial phase, escalating doses of NeoTCR-P1 T cells administered without and with IL-2 in the regimen, and following conditioning chemotherapy, will be evaluated in subjects with advanced or metastatic solid tumors (melanoma, urothelial cancer, colorectal cancer, ovarian cancer, HR+ breast cancer, and prostate cancer). The objective of the Phase 1a study is to establish a recommended Phase 2 dose. Primary endpoints include the incidence and nature of DLTs and overall process feasibility. The proliferation, persistence, and trafficking of NeoTCR-T cells will be characterized. In the expansion trial phase, preliminary anti-tumor activity of NeoTCR-P1 will be assessed in selected tumors. The combination of NeoTCR-P1 dosing plus nivolumab will be tested in a Phase 1b study. Conclusion: This is the first clinical study of an autologous, fully personalized adoptive T cell therapy directed against private tumor-exclusive mutations, generated without using recombinant viral vectors. Clinical trial information: NCT03970382 .

ACS Nano ◽  
2019 ◽  
Vol 13 (2) ◽  
pp. 1469-1478 ◽  
Weidong Nie ◽  
Wei Wei ◽  
Liping Zuo ◽  
Chengliang Lv ◽  
Fan Zhang ◽  

2020 ◽  
Vol 217 (12) ◽  
Shannon K. Oda ◽  
Kristin G. Anderson ◽  
Pranali Ravikumar ◽  
Patrick Bonson ◽  
Nicolas M. Garcia ◽  

Adoptive T cell therapy (ACT) with genetically modified T cells has shown impressive results against some hematologic cancers, but efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs). For example, Fas ligand is commonly overexpressed in TMEs and induces apoptosis in tumor-infiltrating, Fas receptor–positive lymphocytes. We engineered immunomodulatory fusion proteins (IFPs) to enhance ACT efficacy, combining an inhibitory receptor ectodomain with a costimulatory endodomain to convert negative into positive signals. We developed a Fas-4-1BB IFP that replaces the Fas intracellular tail with costimulatory 4-1BB. Fas-4-1BB IFP-engineered murine T cells exhibited increased pro-survival signaling, proliferation, antitumor function, and altered metabolism in vitro. In vivo, Fas-4-1BB ACT eradicated leukemia and significantly improved survival in the aggressive KPC pancreatic cancer model. Fas-4-1BB IFP expression also enhanced primary human T cell function in vitro. Thus, Fas-4-1BB IFP expression is a novel strategy to improve multiple T cell functions and enhance ACT against solid tumors and hematologic malignancies.

2015 ◽  
Vol 26 ◽  
pp. viii1
S. Parviainen ◽  
R. Havunen ◽  
M. Siurala ◽  
S. Tähtinen ◽  
D. Saha ◽  

2011 ◽  
Vol 47 (8) ◽  
pp. 1013-1019 ◽  
P Pedrazzoli ◽  
P Comoli ◽  
D Montagna ◽  
T Demirer ◽  

2018 ◽  
Kristin Anderson ◽  
Shannon Oda ◽  
Breanna Bates ◽  
Edison Chiu ◽  
Christopher Morse ◽  

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