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Abstract
Background Immune checkpoint inhibitors (ICI) revolutionized solid tumor treatment, however, in many tumors only partial response is achieved. Allocetra-OTS has an immune modulating effect on macrophages1 and showed an excellent safety profile in patients including patients with sepsis.2 Here we investigated the anti-tumoral effect of Allocetra-OTS cellular therapy, in solid tumor animal models.
Methods Allocetra-OTS is manufactured from enriched mononuclear fractions and induced to undergo early apoptosis.
In an immunecompetent model, Balb/c mice were inoculated intraperitoneally (IP) with AB12 (mesothelioma) with pLenti-PGK-V5-Luc-Neo and treated with anti-CTLA4 with or without Allocetra-OTS. Mice were monitored daily for clinical score and weekly using IVIS. Kaplan-Meier log rank test was done for survival. For Allocetra-OTS preparation, enriched mononuclear fractions were collected by leukapheresis from healthy eligible human donors and induced to undergo early apoptosis.To follow tumor growth in vivo, HeLa-CD19 cells were stably transduced with pLenti-PGK-V5-Luc-Neo. For CAR preparation, fresh mononuclear cells (MNC) were transfected with CD19-CAR plasmids. SCID-Bg mice were injected IP with human HeLa-CD19 or HeLa-CD19-luciferase cells, 10×10 allocetraOTS or vehicle, and 10×10 CD19-CAR T cells or mock T cells.
Results In immune competent Balb/c mesothelioma model, anti-CTLA4 standalone therapy significantly improved survival from mean 34±9 to 44.9 ±20 days (p<0.05). Similarly, Allocetra-OTS standalone therapy improved survival to 52.3 ±20 days (p<0.02). However, anti-CTLA4 + Allocetra-OTS combination therapy, ameliorated survival to 86.7±20 days (p<0.0001) with complete cancer remission in 60-100% of mice (figure 1 & 2). Similar anti-tumoral effects of Allocetra-OTS were seen in mesothelioma model in a combination therapy with either anti-PD1 or cisplatin.
In the CAR-T model, SCID-Bg mice were sacrificed or died from tumor progression in 30±5 days (range 27–37). CAR T cell therapy significantly improved survival to 55±11 days (p < 0.05 vs MOCK) but Alloctra-OTS further improved survival to 75±10 (p < 0.001) with 20-40% complete remission.
Conclusions During IP tumor progression, Allocetra-OTS as a standalone therapy or in combination with ICI, cisplatin or CAR-T therapy, significantly reduced tumor size and resulted in complete remission in up to100% treated mice.
Based on excellent safety profile in > 40 patients treated in prior clinical trials for sepsis and Covid-19, Phase I/II clinical trial of Allocetra-OTS plus chemotherapy has started and first patient already recruited. A second Phase I/II clinical trial of Allocetra-OTS plus anti-PD1, as a second- and third-line therapy in various cancers, is planned for Q4 2022.
References
Trahtemberg U, Mevorach D. Apoptotic cells induced signaling for immune homeostasis in macrophages and dendritic cells. Front Immunol 2017 Oct 25;8:1356.
Van-Heerden V, Abitbol A, Mevorach D. Allocetra-OTS for sepsis associated cytokine storm. Frontiers in Immunology, Front Immunol. 2021 Sep 30;12:718191.
CTLA4 and Allocetra
CTLA4 and Allocetra