Combining a nanoparticle-mediated immunoradiotherapy with dual blockade of LAG3 and TIGIT improves the treatment efficacy in anti-PD1 resistant lung cancer

Autor: Yun, Hu, Sébastien, Paris, Genevieve, Bertolet, Hampartsoum B, Barsoumian, Kewen, He, Duygu, Sezen, Dawei, Chen, Mark, Wasley, Jordan DA, Silva, Joylise A, Mitchell, Tiffany A, Voss, Fatemeh, Masrorpour, Claudia Kettlun, Leyton, Liangpeng, Yang, Carola, Leuschner, Nahum, Puebla-Osorio, Saumil, Gandhi, Quynh-Nhu, Nguyen, Maria Angelica, Cortez, James W, Welsh
Přispěvatelé: Sezen, Duygu (ORCID 0000-0002-4505-2280 & YÖK ID 170535), Hu, Yun, Paris, Sebastien, Bertolet, Genevieve, Barsoumian, Hampartsoum B., He, Kewen, Chen, Dawei, Wasley, Mark, Da Silva, Jordan, Mitchell, Joylise A., Voss, Tiffany A., Masrorpour, Fatemeh, Leyton, Claudia Kettlun, Yang, Liangpeng, Leuschner, Carola, Puebla-Osorio, Nahum, Gandhi, Saumil, Quynh-Nhu Nguyen, Cortez, Maria Angelica, Welsh, James W., School of Medicine
Rok vydání: 2022
Předmět:
Zdroj: Journal of Nanobiotechnology
ISSN: 1477-3155
DOI: 10.1186/s12951-022-01621-4
Popis: Background: while improvements in immunoradiotherapy have significantly improved outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to immunoradiotherapy is that immune cells may be suppressed via the myriad of different immune checkpoint receptors. Therefore, simultaneous blockade of multiple immune checkpoint receptors may enhance the treatment efficacy of immunoradiotherapy. Methods: we combined NBTXR3-enhanced localized radiation with the simultaneous blockade of three different checkpoint receptors: PD1, LAG3, and TIGIT, and tested the treatment efficacy in an anti-PD1-resistant lung cancer model in mice. 129 Sv/Ev mice were inoculated with fifty thousand alpha PD1-resistant 344SQR cells in the right leg on day 0 to establish primary tumors and with the same number of cells in the left leg on day 4 to establish the secondary tumors. NBTXR3 was intratumorally injected into the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 mu g), alpha LAG3 (200 mu g), and alpha TIGIT (200 mu g) were given to mice by intraperitoneal injections on days 5, 8, 11, 14, 21, 28, 35, and 42. Results: this nanoparticle-mediated combination therapy is effective at controlling the growth of irradiated and distant unirradiated tumors, enhancing animal survival, and is the only one that led to the destruction of both tumors in approximately 30% of the treated mice. Corresponding with this improved response is robust activation of the immune response, as manifested by increased numbers of immune cells along with a transcriptional signature of both innate and adaptive immunity within the tumor. Furthermore, mice treated with this combinatorial therapy display immunological memory response when rechallenged by the same cancer cells, preventing tumor engraftment. Conclusion: our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radio-therapy and simultaneous blockade of multiple immune checkpoint receptors and provide a pre-clinical rationale for investigating its translation into human patients.
This work was supported by Cancer Center Support (Core) Grant CA016672 to The University of Texas MD Anderson Cancer Center; the Goodwin family research fund; the family of M. Adnan Hamed, and the Orr Family Foundation to MD Anderson Cancer Center's Thoracic Radiation Oncology program; an MD Anderson Knowledge Gap award; Nanobiotix.
Databáze: OpenAIRE
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