Enhanced tumor control and survival in preclinical models with adoptive cell therapy preceded by low-dose radiotherapy.

Introduction: Effective infiltration of chimeric antigen receptor T (CAR-T) cells into solid tumors is critical for achieving a robust antitumor response and improving therapeutic outcomes. While CAR-T cell therapies have succeeded in hematologic malignancies, their efficacy in solid tumors remains limited due to poor tumor penetration and an immunosuppressive tumor microenvironment. This study aimed to evaluate the potential of low-dose radiotherapy (LDRT) administered before T-cell therapy to enhance the antitumor effect by promoting CAR-T cell infiltration. We hypothesized that combining LDRT with T-cell therapy would improve tumor control and survival compared to either treatment alone.
Methods: We investigated this hypothesis using two NSG mouse models bearing GSU or CAPAN-2 solid tumors. The mice were treated with engineered CAR-T cells targeting guanyl cyclase-C (GCC) or mesothelin as monotherapy or in combination with LDRT. Additionally, we extended this approach to a C57BL/6 mouse model implanted with MC38-gp100+ cells, followed by adoptive transfer of pmel+ T cells before and after LDRT. Tumor growth and survival outcomes were monitored in all models. Furthermore, we employed atomic force microscopy (AFM) in a small cohort to assess the effects of radiotherapy on tumor stiffness and plasticity, exploring the role of tumor nanomechanics as a potential biomarker for treatment efficacy.
Results: Our results demonstrated enhanced tumor control and prolonged survival in mice treated with LDRT followed by T-cell therapy across all models. The combination of LDRT with CAR-T or pmel+ T-cell therapy led to superior tumor suppression and survival compared to monotherapy, highlighting the synergistic impact of the combined approach. Additionally, AFM analysis revealed significant changes in tumor stiffness and plasticity in response to LDRT, suggesting that the nanomechanical properties of the tumor may be predictive of therapeutic response.
Discussion: The findings of this study highlight the transformative potential of incorporating LDRT as a precursor to adoptive T-cell therapy in solid tumors. By promoting CAR-T and pmel+ T-cell infiltration into the tumor microenvironment, LDRT enhanced tumor control and improved survival outcomes, offering a promising strategy to overcome the challenges associated with CAR-T therapy in solid tumors. Additionally, the changes in tumor nanomechanics observed through AFM suggest that tumor stiffness and plasticity could be biomarkers for predicting treatment outcomes. These results support further investigation into the clinical application of this combined approach to improve the efficacy of cell-based therapies in patients with solid tumors.
Competing Interests: JWW: Accuray (SAB, consulting), Alpine Immune Science (SAB, consulting, equity), Boehringer Ingelheim (SAB, consulting), Checkmate Pharmaceuticals (SAB, consulting, equity), China Medical Tribune (SAB, consulting), Genentech (SAB, consulting), GI Innovation (SAB, consulting), Kezar Life Sciences (consulting, SAB), Legion Healthcare Partners (SAB, consulting), Life Science Dynamic Limited (SAB, consulting), McKesson Corporation (SAB, consulting), Molecular Match (equity), Nanorobotix (SAB, consulting), OligoImmune (founder), Roche (SAB, consulting), Roche Molecular Systems (SAB, consulting), Nanobiotix (Research grant, Travel expenses, SAB), BMS (Research grant), Merck (Research grant), Varian (Research grant, Travel expenses, clinical sponsored research), Reflexion (Research grant, Travel expenses, Stock options, SAB), Hotspot Therapeutics (Research grant), Gilead (Research grant), Novocure (SAB), Oncoresponse (SAB, Stock options), Astra Zeneca (consultant, Research grant), Bayer Healthcare (Research grant), Kiromic (Research grant), Alkermes (Research grant, SAB), Artidis (Research grant), Sciclone (Research grant), Takeda (Research grant), Pebble Life Science (Research grant). HB and NP-O report consulting support from Research Guided Cancer Treatment Consults. Authors KX, CW and JM were employed by Takeda Development Centers Americas Inc. Authors GS, SN, PO, ML and MP were employed by ARTIDIS AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The authors declare that this study received funding from Takeda and was involved in the study design. The authors declare that ARTIDIS funded the tissue nanomechanical analysis from the study funded entirely by Takeda. ARTIDIS personnel was involved in the collection, analysis, interpretation, and writing of the tissue nanomechanical section of this manuscript.
(Copyright © 2024 Puebla-Osorio, Fowlkes, Barsoumian, Xega, Srivastava, Kettlun-Leyton, Nizzero, Voss, Riad, Wong, Huang, Hu, Mitchell, Kim, Rafiq, He, Sezen, Hsu, Masrorpour, Maleki, Leuschner, Cortez, Oertle, Loparic, Plodinec, Markman and Welsh.)