The use of checkpoints inhibitors (CPI) has radically changed the medical practices for cancer treatment. Unfortunately, the activity of CPI depends on a preexisting anti-tumor immune response, limiting their use to a small percentage of patients. It is crucial to propose solutions to prime an effective anti-tumor immune response and convert CPI non-responder patients to responders. Recent preclinical/clinical studies have reported that radiotherapy (RT) acts as an efficient modulator of tumor immunogenicity. RT can set in motion processes facilitating tumor recognition by the immune system. Unfortunately, RT rarely generates a sustained anti-tumor immunity and reduction of metastases burden outside the irradiated area - a phenomenon called ‘abscopal effect’ - is hardly obtained after RT and the toxicity to healthy tissues limits the maximum dose of irradiation delivered to patients. NBTXR3 is composed hafnium oxide nanoparticles (HfO2-NP) designed to increase energy dose deposition from inside the cancer cells. The size, shape and surface charge of HfO2-NP allow strong interactions with cancer cells and persistence within the tumor mass after a single intra-tumor administration during the whole RT treatment. The high electron density of HfO2-NP increases interaction probability with ionizing radiations (when compared to tumor tissues with low electron density), resulting in the enhancement of tumor destruction, compared to RT alone. The recent results of phase III in locally advanced Soft Tissue Sarcoma patients demonstrated the significant superiority and clinical benefits of intratumorally injected HfO2-NP activated by RT to treat cancer compared to RT alone, validating the first-in-class mode of action of NBTXR3. In addition, preclinical studies have reported that HfO2-NP activated by RT can induce an anti-tumor immune-response and an abscopal effect. Here, we explored the ability of RT-activated NBTXR3 to increase the efficacy of anti-PD1 or anti-CTLA4 using abscopal assay in immunocompetent mice. In a first assay, mice were subcutaneously injected with 344SQP (mouse lung cancer) cells on both flanks. Then, right tumors were injected with HfO2-NP (or vehicle) and irradiated (or not), while left tumors remain untreated. Some groups of mice received injections of anti-PD1. The same approach was used with CT26 (mouse colorectal cancer) cells, except that mice received anti-CTLA4. For the 344SQP model, tumor growth analysis revealed that NBTXR3+RT and anti-PD1 treatment allows a better tumor control on both sides, compared to other conditions. For CT26 model, NBTXR3+RT and anti-CTLA4 treatment led to a better tumor growth control on both sides, compared to other conditions. These results suggest that NBTXR3 activated by RT could potentiate the anti-PD1 and anti-CTLA4 efficacy, opening new opportunities for the treatment of patients by combination of NBTXR3+RT+CPI. Citation Format: Yun Hu, Ping Zhang, Audrey Darmon, Maria Angelica Cortez, Sébastien Paris, James Welsh. Enhancement of anti-PD1 and anti-CTLA4 efficacy by NBTXR3 nanoparticles exposed to radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3225.
Background: While improvements in radioimmunotherapy have made significant headway in improving outcomes for cancer patients, this treatment approach has nevertheless proven ineffective at controlling the majority of malignancies. One of the mechanisms of resistance to radioimmunotherapy 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 radioimmunotherapy.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. 129Sv/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 to the primary tumors on day 7, which were irradiated with 12 Gy on days 8, 9, and 10. Anti-PD1 (200 mg), αLAG3 (200 mg), and αTIGIT (200 mg) 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 growth of treated and distant untreated tumors, enhancing animal survival and is the only one that led to complete destruction of both tumors in approximately 30% of treated mice. Corresponding with this improved response is a 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.Conclusions: Our results strongly attest to the efficacy and validity of combining nanoparticle-enhanced radiotherapy and simultaneous blockade of multiple immune check point receptors and provide pre-clinical rationale for investigation into its translation into human patients.
Introduction: Checkpoint inhibition (CPI) has been a game-changer for cancer therapy, but most cancers do not respond. Part of the problem is that cancers employ multiple checkpoints; thus, targeting multiple checkpoint receptors simultaneously may yield increased benefit. Previously, we found that radiotherapy (XRT) in concert with a radiation-enhancing nanoparticle (NBTXR3) and PD1 blockade significantly improved tumor control both at the irradiative site and in remote, unirradiated tumors in a mouse model of anti-PD1 (αPD1)-resistant lung cancer (344SQR). Here, we tested whether blockade of TIGIT, LAG3, and PD1 in combination with NBTXR3-enhanced XRT could improve antitumor immune responses in our 344SQR tumor model. Methods: Fifty thousand 344SQR cells were inoculated in the right and left hindlimbs of 129Sv/Ev mice on day 0 and day 4 to establish primary and secondary tumors, respectively. Mice were divided into six treatment groups: 1) untreated; 2) XRT+αPD1; 3) NBTXR3+XRT+αPD1; 4) NBTXR3+XRT+αPD1+αLAG3; 5) NBTXR3+XRT+αPD1+αTIGIT; and 6) NBTXR3+XRT+αPD1+αLAG3 +αTIGIT. Primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7 and received 3 fractions of 12 Gy X-ray radiation on days 8, 9, and 10. Immune checkpoint inhibitors, composed of αPD1 (200 μg), αLAG3 (200 μg), and αTIGIT (200 μg), were intraperitoneally administered to the mice on days 5, 8, 11, 14. The expression of 770 immune-related genes were measured via NanoString from the RNA extracted from the primary and secondary tumors on day 21. Results: CPIs+NBTXR3-enhanced radiation significantly promoted the upregulation of mRNA transcripts involved in innate immunity, the humoral response, B cell function, dendritic cell (DC) function, and antigen processing within primary, irradiated tumors relative to untreated controls. No additional increase in immune gene activity in the irradiated tumors was observed when LAG3, TIGIT, or both were blocked in addition to PD1. However, within the non-irradiated tumors, triple blockade of PD1, LAG3, and TIGIT in concert with NBTXR3+XRT produced elevations in multiple immune-related pathways that were significantly higher than those produced by other treatment combinations. These pathways included both adaptive and innate immunity; B, T, and natural killer (NK) cell, and DC function; and antigen processing. Conclusions: Simultaneous inhibition of LAG3 and TIGIT in tandem with PD1 blockade and NBTXR3-enhanced radiotherapy promotes immune activation at the irradiated site. In addition, abscopal immune responses are improved with blockade of LAG3 and TIGIT. These results suggest that blockade of multiple immune checkpoints in parallel with NBTXR3-mediated radiotherapy may be effective in metastatic cancers. [Y.H. and B.G. contributed equally to this work.] Citation Format: Yun Hu, Genevieve Bertolet, Sebastien Paris, Hampartsoum Barsoumian, Jordan DA SILVA, Saumil Gandhi, Quynh-Nhu Nguyen, Maria A. Cortez, James W. Welsh. Nanoparticle-enhanced radiotherapy combined with triple blockade of PD1, LAG3, and TIGIT enhances anti-tumor immune activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5516.
Introduction: Immunoradiotherapy combining radiotherapy and immune checkpoint blockade, has achieved impressive treatment outcomes. We have previously demonstrated that photon (XRT) and proton (PRT) localized radiotherapy in combination with immune checkpoint blockade and NBTXR3, a radioenhancing nanoparticle, could induce a systemic antitumor immune response. However, no studies have compared the treatment efficacy of PRT and XRT immunoradiotherapy. Here, we compared the capabilities of PRT and XRT when combined with NBTXR3 and PD1 blockade for inducing an antitumor immune response. Methods: 344SQR cells were inoculated in the right and left hindlimbs of 129Sv/Ev mice on day 0 and day 4 to establish primary and secondary tumors, respectively. Mice were divided into five treatment groups: 1) untreated control; 2) XRT+αPD1; 3) NBTXR3+XRT+αPD1; 4) PRT+αPD1; 5) NBTXR3+PRT+αPD1. The primary tumors were intratumorally injected with NBTXR3 nanoparticles on day 7, followed by two fractions of 12 Gy XRT or PRT on days 8 and 9 (total dose of 24 Gy). Two hundred μg of αPD1 was given to the mice on days 7, 10, 14, 21, 28, 35, and 42 through intraperitoneal injection. We assayed whole tumor RNAs with a Nanostring pan-cancer immune panel to profile the tumor immune microenvironment changes. In addition, immune cells extracted from the tumors were analyzed with single-cell RNA sequencing (scRNAseq). The survivor mice treated with the NBTXR3+PRT+αPD1 were rechallenged with 344SQR and 344SQP cells. Results: PRT+ αPD1 resulted in significantly better control of the primary tumors than XRT+ αPD1. No significant difference was observed in the volume of the secondary tumors treated with XRT+ αPD1 and the control. In contrast, PRT+ αPD1 resulted in a pronounced abscopal effect. Adding NBTXR3 to XRT+ αPD1 and PRT+ αPD1 improved the control of both the primary and secondary tumors. In addition, NBTXR3+PRT+αPD1 achieved significantly slower growth of the two tumors and more prolonged survival than NBTXR3+XRT+αPD1. Remarkably, NBTXR3+PRT+αPD1 eradicated both primary and secondary tumors in 40% of the treated mice, while no mice were cured by NBTXR3+XRT+αPD1. Nanostring analysis and scRNAseq revealed better activation and infiltration of antitumoral immune cells to the two tumors when treated with PRT than XRT. The survivor mice treated with NBTXR3+PRT+αPD1 effectively rejected tumor growth after rechallenge with 344SQR and 344SQP cells. Conclusions: When combined with NBTXR3, PRT with αPD1 exhibited significantly better treatment efficacy than XRT with αPD1. The superior efficacy of NBTXR3+PRT+αPD1 is accompanied by a more robust immune activation and immune cell infiltration in irradiated and unirradiated tumors. Citation Format: Yun Hu, Sébastien Paris, Narayan Sahoo, Qi Wang, Qianxia Wang, Hampartsoum B. Barsoumian, Jordan Da Silva, Célia Bienassis, Ailing Huang, Nahum Puebla-Osorio, Saumil Gandhi, Quynh-Nhu Nguyen, Jing Wang, Maria A. Cortez, James W. Welsh. NBTXR3 radio-enhancing nanoparticle achieves a more robust antitumor immune response when combined with proton radiotherapy than photon radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2415.
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