High Dose Local Photon Irradiation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance the Abscopal Response in a Murine Pancreatic Carcinoma Model

Yamamoto, Junya; Takahashi, Yutaka; Minami, Kazumasa; Tamari, Keisuke; Katsuki, Shohei; Takenaka, Wataru; Tatekawa, Shotaro; Hayashi, Kazuhiko; Seo, Yuji; Isohashi, Fumiaki; Ogawa, Kazuhiko; Koike, Masahiko

doi:10.3390/cancers14092087

Cited by 5 publications

(4 citation statements)

References 41 publications

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“…Alpha radiation treatment appears therefore to induce an immune response through immunogenic cell death, with enhanced efficacy in combination with check-point inhibition. This has been previously reported with other methods of irradiation in combination with check point inhibition ( 47 ).…”

Section: Discussionsupporting

confidence: 81%

Tumor growth inhibition and immune system activation following treatment with thorium-227 conjugates and PD-1 check-point inhibition in the MC-38 murine model

et al. 2022

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Targeted thorium-227 conjugates comprise the combination of a monoclonal antibody with specificity for a tumor cell antigen and a 3,2-HOPO chelator enabling complexation of thorium-227 (Th-227). The radiolabeled conjugate functions as an effective delivery system of alpha-particle radiation to the surface of the tumor cell inducing difficult to repair complex DNA damage and cell death. In addition, the mechanism of action of targeted alpha therapy (TAT) appears to involve a significant component linked to stimulation of the immune system. We report herein evidence of immune activation and long-lasting immune protection of a TAT in a syngeneic model using the MC-38 murine cell line. Firstly, MC-38 cells were irradiated ex vivo with the thorium labeled antibody before subcutaneous implantation into mice. These mice were then rechallenged with MC-38 cells contra-laterally. In the group receiving irradiated cells, 9 out of 10 animals had no measurable tumor growth compared to aggressive tumor growth in the control group. Secondly, in an efficacy study, 500 kBq/kg of thorium labeled antibody alone or in combination with PD-1 checkpoint inhibitor gave statistically significant tumor growth inhibition compared to vehicle control. Animals with no measurable tumors were once again rechallenged contra-laterally with MC-38 cells. The re-growth of tumors was significantly delayed (approx. 60 days) in the treatment group compared to age-matched controls (approx. 30 days) in the monotherapy group. Interestingly, in the TAT/ PD-1 combination group no re-growth was observed demonstrating the potential of combining a TAT with checkpoint inhibition therapy. Finally, tumors were excised from treated mice and analyzed by flow cytometry and immunohistochemistry (IHC). Analysis revealed significant infiltration of CD8+ T-cells and mature dendritic cells compared to vehicle controls. Together these results indicated that an ongoing immune response from treatment with alpha radiation could be enhanced by check-point inhibition.

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Section: Discussionsupporting

confidence: 81%

Tumor growth inhibition and immune system activation following treatment with thorium-227 conjugates and PD-1 check-point inhibition in the MC-38 murine model

et al. 2022

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“…Previous clinical reports demonstrated that neoadjuvant chemoradiotherapy increased the proportion of CD8 + T cells in the whole lymphocytes in other tumors (22,23). A recent preclinical study using a pancreatic ductal carcinoma mouse model demonstrated that local irradiation at 16 Gy in a single fraction and three fractions of 8 Gy increased not only Teff but also Treg in irradiated tumors, indicating that radiation altered the tumor immune microenvironment to immune evasion as well as immune activation (24). Similarly, in a colon cancer mouse model, radiation at 12 Gy in a single fraction clearly promoted the accumulation of Treg (25).…”

Section: Discussionmentioning

confidence: 94%

Biological effects of prostaglandin E2-EP4 antagonist (AAT-008) in murine colon cancer in vivo: enhancement of immune response to radiotherapy and potential as a radiosensitizer

Manabe¹,

Takahashi²,

Sugie³

et al. 2023

Transl Cancer Res

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Background: Prostaglandin E2 (PGE2) promotes tumor growth and metastasis by acting on a family of four receptors (EP1-4). We investigated the radiosensitizing effects of a newly developed antagonist of PGE2-EP4 (AAT-008) in mouse colon cancer cells in vivo and explored the mechanism using flow cytometry (FCM).Methods: CT26WT cells grown in Balb/c mice were used. AAT-008 at doses of 0, 3, 10, and 30 mg/kg/day was orally administered once or twice daily for up to 19 days. On day 3, the tumors were irradiated at 9 Gy in the radiotherapy (RT) group. Tumor sizes were measured every other day. For the first FCM series, AAT-008 (10 mg/kg/day) was administered from day 0 to 18 and RT (9 Gy) was given on day 3. The population of effector T cells (Teff), defined as CD45 + CD8 + CD69 + , in the tumors was investigated on day 19. For the second FCM series, AAT-008 (30 mg/kg/day) was administered from day 0 to 12. The populations of Teff and regulatory T cells (Treg), and the ratio of Teff/Treg were investigated on day 13. Results:The growth delay effect of AAT-008 administered alone (3-30 mg/kg/day) appeared minimal. In the first growth delay experiment where AAT-008 was administered once daily, the combined effect of AAT-008 (30 mg/kg/day) and RT appeared additive. In the second growth delay experiment where AAT-008 was administered twice daily, the combined effect appeared additive at 3 and 10 mg/kg/day and supra-additive at 30 mg/kg/day. In the first FCM series, the mean Teff proportions in the tumors were 43% and 31% in the 10 mg + RT and 0 mg + RT groups, respectively. Notably, 67% Teff was observed in responsive mice in the 10 mg + RT group. In the second FCM series, the mean Treg proportion and Teff/Treg ratio in the 0 mg + RT and 30 mg + RT groups were 4.0% and 1.5%, respectively (P=0.04) and 10 and 22, respectively (P=0.04).Conclusions: AAT-008 potentially enhances the radiosensitivity of colon cancer cells, apparently by stimulating the immune system against the cancer cells.

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“…This was due to IFN-I mediated DC infiltration, CD8 + cross priming, and subsequent effector CD8 + T cell infiltration into the TIME (191,192). Such antitumor response was consistently observed when RT was combined with an anti-CTLA-4 ICI in vivo (193)(194)(195)(196). The intensity of an abscopal response generated from such combinations are dose fractionation and treatment sequence dependent.…”

Section: Augmenting Antitumor Immunity By Combining Radiotherapy With...mentioning

confidence: 97%

“…When compared with concurrent delivery of RT and an anti-CTLA-4 ICI, ICI delivery after RT was shown to have reduced distant therapeutic effect. Increased antitumor immunity with the combined treatment is associated with increased CTLs, CD8/CD4 ratio, reduced Tregs within the TIME, and increased CD8 + T cell clonality ( 195 , 196 ).…”

Section: Augmenting Antitumor Immunity By Combining Radiotherapy With...mentioning

confidence: 99%

Mechanistic rationales for combining immunotherapy with radiotherapy

Chi

Nguyen

2023

Front. Immunol.

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Immunotherapy consisted mainly of immune checkpoint inhibitors (ICIs) has led to significantly improved antitumor response. However, such response has been observed only in tumors possessing an overall responsive tumor immune micro-environment (TIME), in which the presence of functional tumor-infiltrating lymphocytes (TILs) is critical. Various mechanisms of immune escape from immunosurveillance exist, leading to different TIME phenotypes in correlation with primary or acquired resistance to ICIs. Radiotherapy has been shown to induce antitumor immunity not only in the irradiated primary tumor, but also at unirradiated distant sites of metastases. Such antitumor immunity is mainly elicited by radiation’s stimulatory effects on antigenicity and adjuvanticity. Furthermore, it may be significantly augmented when irradiation is combined with immunotherapy, such as ICIs. Therefore, radiotherapy represents one potential therapeutic strategy to restore anti-tumor immunity in tumors presenting with an unresponsive TIME. In this review, the generation of anti-tumor immunity, its impairment, radiation’s immunogenic properties, and the antitumor effects of combining radiation with immunotherapy will be comprehensively discussed.

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High Dose Local Photon Irradiation Is Crucial in Anti-CTLA-4 Antibody Therapy to Enhance the Abscopal Response in a Murine Pancreatic Carcinoma Model

Cited by 5 publications

References 41 publications

Tumor growth inhibition and immune system activation following treatment with thorium-227 conjugates and PD-1 check-point inhibition in the MC-38 murine model

Tumor growth inhibition and immune system activation following treatment with thorium-227 conjugates and PD-1 check-point inhibition in the MC-38 murine model

Biological effects of prostaglandin E2-EP4 antagonist (AAT-008) in murine colon cancer in vivo: enhancement of immune response to radiotherapy and potential as a radiosensitizer

Mechanistic rationales for combining immunotherapy with radiotherapy

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