Adoptive cell therapy using PD-1 + myeloma-reactive T cells eliminates established myeloma in mice

Abstract

Background

Adoptive cellular therapy (ACT) with cancer antigen-reactive T cells following lymphodepletive pre-conditioning has emerged as a potentially curative therapy for patients with advanced cancers. However, identification and enrichment of appropriate T cell subsets for cancer eradication remains a major challenge for hematologic cancers.

Methods

PD-1⁺ and PD-1⁻ T cell subsets from myeloma-bearing mice were sorted and analyzed for myeloma reactivity in vitro. In addition, the T cells were activated and expanded in culture and given to syngeneic myeloma-bearing mice as ACT.

Results

Myeloma-reactive T cells were enriched in the PD-1⁺ cell subset. Similar results were also observed in a mouse AML model. PD-1⁺ T cells from myeloma-bearing mice were found to be functional, they could be activated and expanded ex vivo, and they maintained their anti-myeloma reactivity after expansion. Adoptive transfer of ex vivo-expanded PD-1⁺ T cells together with a PD-L1 blocking antibody eliminated established myeloma in Rag-deficient mice. Both CD8 and CD4 T cell subsets were important for eradicating myeloma. Adoptively transferred PD-1⁺ T cells persisted in recipient mice and were able to mount an adaptive memory immune response.

Conclusions

These results demonstrate that PD-1 is a biomarker for functional myeloma-specific T cells, and that activated and expanded PD-1⁺ T cells can be effective as ACT for myeloma. Furthermore, this strategy could be useful for treating other hematologic cancers.

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