Safety and efficacy of Sleeping Beauty TCR-T cells targeting shared KRAS and TP53 mutations expressed by solid tumors in first-in-human phase 1 study.
Authors: Morelli Maria Pia , Negrao Marcelo Vailati , Collinson-Pautz Matthew R. , Jernigan Kamisha , Demars Nathan A. , Weitzman Aaron , Adeyemi Frances , Carpio Victor H , Jazaeri Amir A. , Johnson Benny , Pant Shubham , Kebriaei Partow , Srivastava Abhishek K , Deniger Drew Caldwell , Heymach John , Kopetz Scott 
Published: June 2023

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Background: Solid tumors present driver mutations in KRAS, TP53, and EGFR genes on their surface in the context of human leukocyte antigen (HLA) molecules to T-cell receptors (TCRs) expressed by T cells. Non-viral genetic engineering of patient T cells with the Sleeping Beauty transposon/transposase system can generate driver mutation-reactive TCR-T cells. Methods: This is a first-in-human phase 1/2 study of autologous Sleeping Beauty TCR-T cell therapy for patients with non-small cell lung (NSCLC), colorectal, endometrial, pancreatic, ovarian and bile duct cancer whose tumors contain at least one of the targeted driver mutations in KRAS, TP53, and EGFR. The primary objective of the phase 1 portion is to define the incidence of dose-limiting toxicities (DLTs) and the maximum tolerated dose or recommended phase 2 dose to be explored in disease specific cohorts during phase 2. Dose levels of 0.1-1 x 1010 (DL1), 1-7 x 1010 (DL2) or 7-15 x 1010 (DL3) TCR-T cells are being explored. Any of the six tumor types or 12 TCRs within the library can be used for the Phase 1 portion of the trial. Results: As of February 14, 2023, three patients have been treated with Sleeping Beauty TCR-T cells on this study. The first was a 34 year old female with stage IV mucinous adenocarcinoma NSCLC refractory to chemotherapy and immunotherapy who received DL1 (0.9 x 1010 TCR-T cells) targeting KRASG12D and HLA-A*11:01, second was a 54 year old female with stage IVA chemotherapy resistant colorectal cancer who received DL2 (6.4 x 1010 TCR-T cells) targeting p53R175H and HLA-A*02:01 and the third was a 60 year old male with stage IV pancreatic cancer refractory to chemotherapy who received DL2 (5.8 x 1010 TCR-T cells) targeting KRASG12V and HLA-A*11:01. Overall, a manageable safety profile with no unexpected adverse events, DLTs or immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Patients 1, 2 and 3 had cytokine release syndrome grades 2, 3 and 1, respectively, that were self-limiting or resolved with standard management and anti-IL-6 antibody in the case of Patient 2. Best overall responses were partial response for Patient 1 with six month progression-free survival, stable disease for Patient 2 and progressive disease for Patient 3. Persistence of TCR-T cells was observed in all patients at last follow-up and out to 6 months in the case of Patient 1. Acceleration to DL3 is under consideration based on a continued manageable safety profile. Conclusions: This is the first-in-human experience administering Sleeping Beauty TCR-T cells. Signs of efficacy, safety and persistence of TCR-T cells was observed. Thus, this treatment has promise for patients with solid tumors expressing shared mutations in driver genes. The trial is actively enrolling new patients and treating at one of the two highest dose levels. Clinical trial information: NCT05194735 .