Massive clonal expansion of medulloblastoma-specific T cells during adoptive cellular therapy.

in Science advances by C Flores, T Wildes, B DiVita Dean, G Moore, J Drake, R Abraham, J Gil, O Yegorov, C Yang, J Dean, C Moneypenny, D Shin, C Pham, J Krauser, J King, G Grant, T Driscoll, J Kurtzberg, R McLendon, S Gururangan, D Mitchell

TLDR

  • The study developed an adoptive cellular therapy platform against medulloblastoma and glioblastoma using dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors. The study found that an early and massive expansion of tumor-reactive lymphocytes, coupled with prolonged persistence in the peripheral blood, is observed during effective therapeutic response to immunotherapy treatment. The study suggests that future research directions could include the development of personalized adoptive cellular therapy platforms that utilize tumor-specific RNA transcriptomes to expand tumor-reactive T cells.

Abstract

In both human and murine systems, we have developed an adoptive cellular therapy platform against medulloblastoma and glioblastoma that uses dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors. We demonstrate that peripheral TCR Vβ repertoire analysis after adoptive cellular therapy reveals that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood. In preclinical models of medulloblastoma and glioblastoma, and in a patient with relapsed medulloblastoma receiving adoptive cellular therapy, an early and massive expansion of tumor-reactive lymphocytes, coupled with prolonged persistence in the peripheral blood, is observed during effective therapeutic response to immunotherapy treatment.

Overview

  • The study focuses on developing an adoptive cellular therapy platform against medulloblastoma and glioblastoma using dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors. The hypothesis being tested is that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood. The methodology used for the experiment includes the use of human and murine systems, and preclinical models of medulloblastoma and glioblastoma, as well as a patient with relapsed medulloblastoma receiving adoptive cellular therapy. The primary objective of the study is to demonstrate that an early and massive expansion of tumor-reactive lymphocytes, coupled with prolonged persistence in the peripheral blood, is observed during effective therapeutic response to immunotherapy treatment.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions or interventions detailed in the study. The results show that an early and massive expansion of tumor-reactive lymphocytes, coupled with prolonged persistence in the peripheral blood, is observed during effective therapeutic response to immunotherapy treatment. The study identifies that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood. The key findings of the study are that adoptive cellular therapy platform against medulloblastoma and glioblastoma using dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors is effective in expanding tumor-reactive lymphocytes and that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study demonstrates that an effective adoptive cellular therapy platform against medulloblastoma and glioblastoma using dendritic cells pulsed with a tumor RNA transcriptome to expand polyclonal tumor-reactive T cells against a plurality of antigens within heterogeneous brain tumors is effective in expanding tumor-reactive lymphocytes. The study identifies that effective response to adoptive cellular therapy is concordant with massive in vivo expansion and persistence of tumor-specific T cell clones within the peripheral blood. The study suggests that future research directions could include the development of personalized adoptive cellular therapy platforms that utilize tumor-specific RNA transcriptomes to expand tumor-reactive T cells. The study also suggests that future research directions could include the development of adoptive cellular therapy platforms that utilize tumor-specific RNA transcriptomes to expand tumor-reactive T cells in combination with other immunotherapies, such as checkpoint inhibitors, to enhance therapeutic efficacy.
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