Abstract
Purpose: Current understanding of resistance to CAR-T cell therapy in solid tumors implicates inadequate CAR-T cell potency in the immunosuppressive tumor microenvironment (TME). We have previously developed a platform using somatostatin receptor 2 (SSTR2) as a positron emission tomography (PET) reporter to detect CAR-T cell expansion and trafficking. The current study aimed to leverage SSTR2 for low-dose targeted radionuclide therapy (177Lu-DOTATATE, Lutathera), which under dosimetry guidance might enhance antitumor immunity by reprograming the TME and promoting T-cell reinvigoration.
Methods: Using intercellular adhesion molecule 1 (ICAM-1) as a model antigen, we evaluated the immunomodulatory effects of low-dose radiation in a gastric cancer animal model. NSG mice were inoculated subcutaneously with firefly luciferase-expressing Hs 746T cells (0.1 × 106 per mouse) and treated 5 days later with 10 × 106 SSTR2-expressing ICAM-1 CAR-T cells. CAR-T cell expansion was monitored weekly by PET scan using 18F-NOTA-Octreotide, a radiotracer targeting SSTR2. Three weeks post-T cell infusion, a cohort of mice were injected with 7.4 MBq of 177Lu-DOTATATE via the tail vein. SPECT imaging was performed for dosimetry analysis. Tumor growth was monitored by bioluminescence imaging and tumor size measurement. Serum cytokines were analyzed.
Results: Single dose 177Lu-DOTATATE treatment (delivering 1-6 Gy to tumor) improved response of established gastric cancer tumor (>1,000 mm3) that was not responsive to CAR-T cell treatment alone and significantly prolonged survival. All mice receiving CAR-T cells plus 177Lu-DOTATATE displayed rapid tumor shrinkage, with 83% of mice achieving complete remission within 3 weeks of 177Lu-DOTATATE treatment. SPECT imaging confirmed specific delivery of 177Lu-DOTATATE by tumor-infiltrating CAR-T cells, with tumor uptake of 0.43 ± 0.24 and 0.19 ± 0.08 MBq/g at 24 and 144 hours post 177Lu-DOTATATE injection, respectively. Most radioactivity reduction over time (73%) is explained by physical decay of 177Lu, indicating persistent tumor retention of 177Lu-DOTATATE. In contrast, rapid clearance of 177Lu-DOTATATE was observed in liver and kidneys. Importantly, longitudinal CAR-T cell imaging using 18F-NOTA-Octreotide revealed increased CAR-T cell expansion induced by low-dose radiation. Furthermore, we detected high levels of IFN-γ and perforin in serum after 177Lu-DOTATATE treatment, which were >10 folds higher than that in control mice receiving CAR-T cell only, indicating activation of T cells by low-dose radiation.
Conclusions: We developed a translatable radioimmunotherapy platform that incorporates a FDA-approved theranostic endoradiotherapy (Lutathera) to improve tumor response to CAR-T cell therapy. The next steps would be to explore the immunomodulatory effects of low-dose radiation systematically and elucidate the mechanism of action.
Methods: Using intercellular adhesion molecule 1 (ICAM-1) as a model antigen, we evaluated the immunomodulatory effects of low-dose radiation in a gastric cancer animal model. NSG mice were inoculated subcutaneously with firefly luciferase-expressing Hs 746T cells (0.1 × 106 per mouse) and treated 5 days later with 10 × 106 SSTR2-expressing ICAM-1 CAR-T cells. CAR-T cell expansion was monitored weekly by PET scan using 18F-NOTA-Octreotide, a radiotracer targeting SSTR2. Three weeks post-T cell infusion, a cohort of mice were injected with 7.4 MBq of 177Lu-DOTATATE via the tail vein. SPECT imaging was performed for dosimetry analysis. Tumor growth was monitored by bioluminescence imaging and tumor size measurement. Serum cytokines were analyzed.
Results: Single dose 177Lu-DOTATATE treatment (delivering 1-6 Gy to tumor) improved response of established gastric cancer tumor (>1,000 mm3) that was not responsive to CAR-T cell treatment alone and significantly prolonged survival. All mice receiving CAR-T cells plus 177Lu-DOTATATE displayed rapid tumor shrinkage, with 83% of mice achieving complete remission within 3 weeks of 177Lu-DOTATATE treatment. SPECT imaging confirmed specific delivery of 177Lu-DOTATATE by tumor-infiltrating CAR-T cells, with tumor uptake of 0.43 ± 0.24 and 0.19 ± 0.08 MBq/g at 24 and 144 hours post 177Lu-DOTATATE injection, respectively. Most radioactivity reduction over time (73%) is explained by physical decay of 177Lu, indicating persistent tumor retention of 177Lu-DOTATATE. In contrast, rapid clearance of 177Lu-DOTATATE was observed in liver and kidneys. Importantly, longitudinal CAR-T cell imaging using 18F-NOTA-Octreotide revealed increased CAR-T cell expansion induced by low-dose radiation. Furthermore, we detected high levels of IFN-γ and perforin in serum after 177Lu-DOTATATE treatment, which were >10 folds higher than that in control mice receiving CAR-T cell only, indicating activation of T cells by low-dose radiation.
Conclusions: We developed a translatable radioimmunotherapy platform that incorporates a FDA-approved theranostic endoradiotherapy (Lutathera) to improve tumor response to CAR-T cell therapy. The next steps would be to explore the immunomodulatory effects of low-dose radiation systematically and elucidate the mechanism of action.
| Original language | English (US) |
|---|---|
| Title of host publication | Cancer Research |
| Volume | 83 (7_Supplement): 5084 |
| State | Published - Apr 4 2023 |
| Event | AACR Annual Meeting 2023 - Orlando, United States Duration: Apr 14 2023 → Apr 19 2023 |
Conference
| Conference | AACR Annual Meeting 2023 |
|---|---|
| Country/Territory | United States |
| City | Orlando |
| Period | 4/14/23 → 4/19/23 |