What question did this study set out to answer?

To assess the efficacy of high-LET radiation approaches combined with PD-1 inhibitors in improving treatment outcomes for pMMR rectal cancer.

April 5, 2026

Abstract 2569: Particle therapy, ATM and PD-1 inhibition for pMMR rectal cancer

Key Points

To assess the efficacy of high-LET radiation approaches combined with PD-1 inhibitors in improving treatment outcomes for pMMR rectal cancer.
In vitro proton irradiation of various colorectal cancer cell lines to measure responses to treatment.
Balb/C mice were inoculated with cancer cells to establish tumor models for in vivo experimentation.
Administration of PD-1 inhibitors and ATM inhibitors alongside radiation therapy to assess combined effects.
Mass cytometry was used to analyze immune cell population changes in the tumor microenvironment.
DaRT and BP protons combined with ATM inhibitors significantly increased complete response rates in primary and abscopal tumors.
The combination treatments enhanced DNA damage and activated innate immune pathways while reducing immunosuppression.
These effects were noted in a pMMR model that previously did not respond to conventional therapies.

Abstract

Abstract Background and Aims: Colorectal cancer is a leading cause of cancer mortality and most rectal cancers are mismatch repair proficient (pMMR), making them largely resistant to PD-1 inhibitors (PD1i). While PD1i achieves excellent complete response rates in MMR-deficient tumors, these represent 5% of rectal cancers. For the remaining 95% of patients, effective immunotherapy strategies are urgently needed. We evaluated two high-LET radiation approaches to prime pMMR rectal cancers to PD1i and enhance local control: 1) Diffusing alpha emitter Radiation Therapy (DaRT) implants, and 2) LET-optimized (Bragg Peak) protons + ATM inhibitor. An ATM inhibitor was evaluated with protons to evaluate whether it could produce a more alpha/carbon-like effect given the lower comparative LETd achievable in clinical treatment plans. Methods: In vitro proton irradiation of HCT116, HT29, SW480, and CT26 was performed as previously with dose averaged LET (LETd) values of 2. 2 keV/um for ENT and 7. 0 keV/um for BP protons. Female Balb/C mice were subcutaneously inoculated with 1×10⁶ CT26 cells on one flank and 1×10⁵ cells on the contralateral flank to establish primary and secondary (abscopal) tumors, respectively. PD1i monoclonal antibody (RMP1-14 Bio X Cell) was administered i. p. 100ug every 72 hours for 4 total doses. The ATM inhibitor AZD1390 was delivered via oral gavage at 20 mg/kg, PO 1 hour prior to radiation. For in vivo studies, radiation was delivered using a PXI SmART small animal irradiator with opposing lateral beams (225 kVp, 20 mA, 0. 3mm Cu filter). Proton irradiation plans were produced as previously described. We used mass cytometry by time of flight (CyTOF) using the TME CD45 lymphocyte subpopulations based on multiple cell markers. Result: In our preliminary data we demonstrate that both DaRT and BP protons+ATMi synergize with PD1i to dramatically increase complete response rates at both primary and abscopal tumors by increasing DNA damage, activating innate immune pathways, and reducing immunosuppression within the tumor microenvironment. Critically, this effect was observed in a pMMR model which did not respond to PD1i or conventional X-rays+PD1i, highlighting the innovation and potential impact of this work. Conclusion: DaRT and BP protons ATMi prime pMMR colorectal cancer to PD1i, and all elements are clinically translatable. Citation Format: Cameron M. Callaghan. Particle therapy, ATM and PD-1 inhibition for pMMR rectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (7 Suppl): Abstract nr 2569.

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Cite This Study

Cameron M. Callaghan (Fri,) studied this question.

synapsesocial.com/papers/69d1fdbfa79560c99a0a3fb8 https://doi.org/https://doi.org/10.1158/1538-7445.am2026-2569

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