Differential combination immunotherapy requirements for inflamed (warm) tumors versus T cell excluded (cool) tumors: engage, expand, enable, and evolve

Abstract

BackgroundDifferent types of tumors have varying susceptibility to immunotherapy and hence require different treatment strategies; these cover a spectrum ranging from ‘hot’ tumors or those with high mutational burden and immune infiltrates that are more amenable to targeting to ‘cold’ tumors that are more difficult to treat due to the fewer targetable mutations and checkpoint markers. We hypothesized that an effective anti-tumor response requires multiple agents that would (1) engage the immune response and generate tumor-specific effector cells; (2) expand the number and breadth of the immune effector cells; (3) enable the anti-tumor activity of these immune cells in the tumor microenvironment; and (4) evolve the tumor response to widen immune effector repertoire.MethodsA hexatherapy combination was designed and administered to MC38-CEA (warm) and 4T1 (cool) murine tumor models. The hexatherapy regimen was composed of adenovirus-based vaccine and IL-15 (interleukin-15) superagonist (N-803) to engage the immune response; anti-OX40 and anti-4-1BB to expand effector cells; anti-PD-L1 (anti-programmed death-ligand 1) to enable anti-tumor activity; and docetaxel to promote antigen spread. Primary and metastatic tumor growth inhibition were measured. The generation of anti-tumor immune effector cells was analyzed using flow cytometry, ELISpot (enzyme-linked immunospot), and RNA analysis.ResultsThe MC38-CEA and 4T1 tumor models have differential sensitivities to the combination treatments. In the ‘warm’ MC38-CEA, combinations with two to five agents resulted in moderate therapeutic benefit while the hexatherapy regimen outperformed all these combinations. On the other hand, the hexatherapy regimen was required in order to decrease the primary and metastatic tumor burden in the ‘cool’ 4T1 model. In both models, the hexatherapy regimen promoted CD4+ and CD8+ T cell proliferation and activity. Furthermore, the hexatherapy regimen induced vaccine-specific T cells and stimulated antigen cascade. The hexatherapy regimen also limited the immunosuppressive T cell and myeloid derived suppressor cell populations, and also decreased the expression of exhaustion markers in T cells in the 4T1 model.ConclusionThe hexatherapy regimen is a strategic combination of immuno-oncology agents that can engage, expand, enable, and evolve the immune response and can provide therapeutic benefits in both MC38-CEA (warm) and 4T1 (cool) tumor models.

From Immunogenic Cell Death to Immunogenic Modulation: Select Chemotherapy Regimens Induce a Spectrum of Immune-Enhancing Activities in the Tumor Microenvironment

“…For effective immunotherapy it is necessary to target four different modes of the tumor-immune system interaction. Immunotherapy strategies must induce a tumor antigen-specific T-cell population, expand the number of antigen-specific T cells and promote their migration to the tumor microenvironment, enable a prolonged immune response, and ensure an evolving immune response to prevent tumor escape ( 15 , 16 ). Depending on the mechanisms engaged, immunogenic cell stress can induce antigen-specific T cells through immunogenic cell death or enable increased immune cell killing of tumor cells through immunogenic modulation.…”

Anti-CTLA-4 and anti-PD-1 immunotherapies repress tumor progression in preclinical breast and colon model with independent regulatory T cells response

“…The 4T1 and CT26 models are described to belong to tumors with differential immunoscore level. Indeed, the 4T1 model could be considered as a ‘cold’ phenotype with low response to immunotherapies [65] , despite the CT26 could be considered as a ‘hot’ phenotype with good response to immunotherapies [66] . Altogether these data might participate to explain the immunotherapy response observed in this work and in clinical observations.…”

Case Report: Pulmonary Metastases From Epithelioid Sarcoma in Extremity Favourably Responding to Immunotherapy With Camrelizumab

“…Finally, whether prior transient administration of pazopanib facilitated the rapid remission of pulmonary metastases in our case, remains unknown. This would be a subject worthy of further exploration, as multiple agents initiate, remodel, and promote the immune response that provides therapeutic benefits in patients with solid tumours (38).…”