Publication Date:
2018-11-29
Description:
Tumor antigen directed T-cells, using chimeric antigen receptors (CAR), have shown remarkable clinical responses in B-cell malignancies, particularly acute lymphoblastic leukemia, diffuse large B-cell lymphoma and multiple myeloma. A number of challenges remain, however, in safe and effective cell therapy for durable responses broadly in hematologic malignancies and solid tumors. The durability of response is often reduced by antigen positive or antigen negative escape while the immunosuppressive tumor microenvironment can reduce the potency of the engineered T-cells. Cytokines can be effectively used to improve T-cell expansion and persistence to prevent antigen positive escape, enhance epitope spreading to prevent antigen negative escape, and to relieve the immunosuppressive tumor microenvironment. Indeed, anti-tumor responses with cytokine immunotherapy as well as cytokine-aided cell therapy have been observed. However, the utility of cytokines is often limited by systemic toxicity associated with their potent pharmacological effects. Locally restricted, on demand production of cytokines coupled with antigen directed T-cells can enable safe and effective cell therapy for the treatment of hematologic malignancies as well as solid tumors. Among the cytokines, Interleukin 12 (IL12) and Interleukin 15 (IL15) are of particular interest due to their role in remodeling the tumor microenvironment and improving T-cell persistence. To determine the effect of cytokine expression on CAR-T control of tumor growth, we generated bicistronic constructs expressing CD19-CAR and IL12 or CD19-CAR and membrane bound IL15 (mbIL15). The constructs were configured to provide a high level of CAR expression with high or low levels of cytokine expression for dose exploration. Even at low cytokine levels and low cell dose, expression of IL12 along with CD19-CAR in human T-cells durably regressed disseminated CD19+ Nalm6-luc tumors in Nod-scid IL2Rgnull (NSG mice), compared to CD19-CAR-expressing cells alone and improved survival at both low and high doses (n=8/group, p
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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