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

Get Permission

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.




By continuing to browse this site you permit us and our partners to place identification cookies on your browser and agree to our use of cookies to identify you for marketing. Read our Privacy Policy to learn more.