Radiation Therapy Enhanced by NBTXR3 Nanoparticles Overcomes Anti-PD1 Resistance and Evokes Abscopal Effects

Hu, Yun; Paris, Sébastien; Barsoumian, Hampartsoum B.; Abana, Chike O.; He, Kewen; Wasley, Mark; Younes, A.; Masrorpour, Fatemeh; Chen, Fan; Yang, Liangpeng; Dunn, Joe Dan; Zhang, Jie; Gandhi, Saumil; Nguyen, Quynh‐Nhu; Cortez, María Angélica; Welsh, James W.

doi:10.1016/j.ijrobp.2021.06.041

Cited by 41 publications

(57 citation statements)

References 30 publications

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“…1 B). Further, consistent with our previous findings [ 11 ], primary tumors treated with both NBTXR3 and radiation grew more slowly than those treated with radiation alone ( P < 0.0001; Fig. 1 B).…”

Section: Resultssupporting

confidence: 92%

“…To determine whether there was any difference in the diversity of the repertoires due to NBTXR3, we analyzed the normalized Shannon clonality indices between the NBTXR3 groups and their non-NBTXR3 counterparts but observed no differences in diversity for both CDR3β and CDR3α sequences (Additional file 2 : Fig. S2), confirming our previous findings [ 11 ]. As a result, we hypothesized that the NBTXR3-induced tumor control that we observed in all NBTXR3-treated mice was likely mediated by tumor-specific T cells shared among the NBTXR3-treated mice.…”

Section: Resultssupporting

confidence: 84%

“…The five treatment groups were as follows: untreated (control), HDXRT + ICIs, HDXRT + LDXRT + ICIs, NBTXR3 + HDXRT + ICIs, and NBTXR3 + HDXRT + LDXRT + ICIs, with treatment conditions defined as follows. As described in a previous study [ 11 ], primary tumors of the HDXRT groups were treated with 3 fractions of 12 Gy each, delivered with an X-RAD 225Cx small-animal irradiator on days 7, 8, and 9 (total dose 36 Gy). The secondary tumors of the LDXRT groups were treated with 2 fractions of 1 Gy each, also delivered with an X-RAD 225Cx small-animal irradiator on day 12 and 13 (total dose 2 Gy).…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from secondary tumors on day 19. TCR sequencing was performed by a method described in a previous study [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

“…NBTXR3, which has been approved for the treatment of localized sarcoma [ 8 ], increases radiation-mediated damage to cancer cells and promotes activation of the STING pathway [ 9 , 10 ], both of which could contribute to immune priming. We further found that the addition of NBTXR3 to radiation-plus-checkpoint blockade therapy also promoted abscopal effects in the metastatic lung cancer model [ 11 ]. However, that combination of localized radiation, NBTXR3, and immunotherapy did not completely eradicate the tumors.…”

Section: Introductionmentioning

confidence: 99%

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A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

Paris

Barsoumian

et al. 2021

J Nanobiotechnol

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Background Combining radiotherapy with PD1 blockade has had impressive antitumor effects in preclinical models of metastatic lung cancer, although anti-PD1 resistance remains problematic. Here, we report results from a triple-combination therapy in which NBTXR3, a clinically approved nanoparticle radioenhancer, is combined with high-dose radiation (HDXRT) to a primary tumor plus low-dose radiation (LDXRT) to a secondary tumor along with checkpoint blockade in a mouse model of anti-PD1-resistant metastatic lung cancer. Methods Mice were inoculated with 344SQR cells in the right legs on day 0 (primary tumor) and the left legs on day 3 (secondary tumor). Immune checkpoint inhibitors (ICIs), including anti-PD1 (200 μg) and anti-CTLA4 (100 μg) were given intraperitoneally. Primary tumors were injected with NBTXR3 on day 6 and irradiated with 12-Gy (HDXRT) on days 7, 8, and 9; secondary tumors were irradiated with 1-Gy (LDXRT) on days 12 and 13. The survivor mice at day 178 were rechallenged with 344SQR cells and tumor growth monitored thereafter. Results NBTXR3 + HDXRT + LDXRT + ICIs had significant antitumor effects against both primary and secondary tumors, improving the survival rate from 0 to 50%. Immune profiling of the secondary tumors revealed that NBTXR3 + HDXRT + LDXRT increased CD8 T-cell infiltration and decreased the number of regulatory T (Treg) cells. Finally, none of the re-challenged mice developed tumors, and they had higher percentages of CD4 memory T cells and CD4 and CD8 T cells in both blood and spleen relative to untreated mice. Conclusions NBTXR3 nanoparticle in combination with radioimmunotherapy significantly improves anti-PD1 resistant lung tumor control via promoting antitumor immune response. Graphical Abstract

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Section: Resultssupporting

confidence: 92%

Section: Resultssupporting

confidence: 84%

Section: Methodsmentioning

confidence: 99%

“…Total RNA was extracted from secondary tumors on day 19. TCR sequencing was performed by a method described in a previous study [ 11 ].…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

Paris

Barsoumian

et al. 2021

J Nanobiotechnol

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High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

et al. 2022

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Different from conventional vaccines, in situ vaccination could conveniently convert established tumors into a "vaccine factory" to release various tumor antigens for stimulating and diversifying antitumor T-cell response. [3] Radiation therapy (RT) is a widely used local therapy of malignancies and exhibits great potential in inducing in situ tumor vaccine effect. [4] However, even potentiated by CBI, RT could only lead to mild to moderate immune response within nonirradiated tumors, which is far less than medical needs. [5] Therefore, it is quite meaningful to boost RT-mediated in situ vaccination to extend its therapeutic effect to the whole body.To achieve this goal, a possible way could be potentiating RT-induced immunogenic cell death (ICD). ICD is a death modality accompanied by releasing tumor antigens and damage-associated molecular patterns, including calreticulin (CRT), high mobility group protein B1 (HMGB1), etc., which could provide antigens and adjuvants for tumor vaccination. [6] Currently, some studies have indicated that oxidative stress and DNA damage within tumor cells could potentially result in ICD. [7] However, due to the insufficient deposition of X-ray within tumor tissues, only low level of reactive oxygen species (ROS) could be produced to induce oxidative stress upon the recommended radiation doses. To address this problem, radiosensitizers based on high-Z elements are being developed widely to deposit X-ray for amplifying RT-induced oxidative stress. Of note, HfO 2 nanoparticles (Hensify) have been approved in Europe for locally advanced soft tissue sarcoma treatment [8] and are confirmed to augment RT-mediated antitumor immunity effect in many clinical trials. However, their slight improvements suggest the room for optimization. [9] The pentose phosphate pathway (PPP) is a branch of glycolysis and hyperactive in most tumors, [10] which could provide abundant NADPH and ribose 5-phosphate to maintain redox and nucleotides homeostasis, respectively. [11] NADPH is a central player in cellular antioxidant system, which not only mediates GSH synthesis, [12] but also acts as an electron donor to reduce oxidized GSH and thioredoxin (Trx, an important In situ tumor vaccination is preliminarily pursued to strengthen antitumor immune response. Immunogenic tumor cell death spontaneously releases abundant antigens and adjuvants for activation of dendritic cells, providing a paragon opportunity for establishing efficient in situ vaccination. Herein, Phy@PLGdH nanosheets are constructed by integrating physcion (Phy, an inhibitor of the pentose phosphate pathway (PPP)) with layered gadolinium hydroxide (PLGdH) nanosheets to boost radiation-therapy (RT)-induced immunogenic cell death (ICD) for potent in situ tumor vaccination. It is first observed that sheet-like PLGdH can present superior X-ray deposition and tumor penetrability, exhibiting improved radiosensitization in vitro and in vivo. Moreover, the destruction of cellular nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide...

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A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy

et al. 2022

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Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2′,3′‐cyclic guanosine monophosphate–adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects. Herein, a 2D nanoplatform, cGAMP/MOL, is reported via conjugating cGAMP to a nanoscale metal–organic layer (MOL) for simultaneous STING activation and radiosensitization. The MOL not only exhibits strong radiosensitization effects for enhanced cancer killing and induction of immunogenic cell death, but also retains cGAMP in tumors for sustained STING activation. Compared to free cGAMP, cGAMP/MOL elicits stronger STING activation and regresses local tumors upon X‐ray irradiation. Further combination with an immune checkpoint inhibitor bridges innate and adaptive immune systems by activating the tumor microenvironment to elicit systemic antitumor responses.

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Radiation Therapy Enhanced by NBTXR3 Nanoparticles Overcomes Anti-PD1 Resistance and Evokes Abscopal Effects

Cited by 41 publications

References 30 publications

A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

A radioenhancing nanoparticle mediated immunoradiation improves survival and generates long-term antitumor immune memory in an anti-PD1-resistant murine lung cancer model

High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy

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