Ex Vivo Manipulation of Tumor Microenvironment Improves Expansion of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy

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In a study reported in Clinical Cancer Research, Chacon and colleagues found that ex vivo manipulation of the tumor microenvironment could enhance expansion of tumor-infiltrating lymphocytes for use in adoptive cell therapy.

The addition of an agonistic anti–4-1BB antibody during initial tumor fragment culture to provide in situ 4-1BB costimulation resulted in activation of 4-1BB signaling in early cultured tumor fragments and acceleration of the rate of outgrowth of memory CD8-positive tumor-infiltrating lymphocytes, which were highly enriched for melanoma antigen specificity.

This was accompanied by nuclear factor (NF)κB activation, induction of T-cell survival and memory genes, and enhanced interleukin-2 responsiveness in CD8-positive T cells in and emerging from the tumor ­fragments.

Early addition of 4-1BB costimulation also promoted dendritic cell maturation in tumor fragments by activating NFκB in the dendritic cells. Blocking of HLA class I prevented the enhanced outgrowth of CD8-positive T cells with anti–4-1BB, indicating that ongoing HLA class I–mediated antigen presentation in early tumor fragment cultures plays a role in influencing tumor-specific CD8-positive tumor-infiltrating lymphocyte outgrowth.

The investigators concluded: “Our results highlight a previously unrecognized concept in tumor-infiltrating lymphocyte [adoptive cell therapy] that the tumor microenvironment can be dynamically regulated in the initial tumor fragment cultures to regulate the types of T cells expanded and their functional characteristics.” ■

Chacon JA, et al: Clin Cancer Res 21:611-621, 2015.