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

Autor: Hu Y; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Paris S; Department of Translational Science, Nanobiotix, Paris, France., Bertolet G; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Barsoumian HB; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., He K; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China., Sezen D; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.; Department of Radiation Oncology, Koc University School of Medicine, Istanbul, Turkey., Chen D; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA.; Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China., Wasley M; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Silva JD; Department of Translational Science, Nanobiotix, Paris, France., Mitchell JA; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Voss TA; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Masrorpour F; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Leyton CK; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Yang L; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Leuschner C; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Puebla-Osorio N; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Gandhi S; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Nguyen QN; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Cortez MA; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA., Welsh JW; Department of Radiation Oncology, Unit 97, The University of Texas MD Anderson Cancer, 1515 Holcombe Blvd, Houston, TX, 77030, USA. jwelsh@mdanderson.org.
Jazyk: angličtina
Zdroj: Journal of nanobiotechnology [J Nanobiotechnology] 2022 Sep 19; Vol. 20 (1), pp. 417. Date of Electronic Publication: 2022 Sep 19.
DOI: 10.1186/s12951-022-01621-4
Abstrakt: 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 αPD1-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 µg), αLAG3 (200 µg), and αTIGIT (200 µg) 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 radiotherapy and simultaneous blockade of multiple immune checkpoint receptors and provide a pre-clinical rationale for investigating its translation into human patients.
(© 2022. The Author(s).)
Databáze: MEDLINE
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