Journal Article

Co-Stimulation through 4-1BB/CD137 Improves the Expansion and Function of CD8+ Melanoma Tumor-Infiltrating Lymphocytes for Adoptive T-Cell Therapy

Sarnaik, Amod, Sukhumalchandra, Pariya, Hwu, Patrick, Wu, Richard C., Weber, Jeffrey, Radvanyi, Laszlo, Chacon, Jessica Ann, Molldrem, Jeffrey J., Pilon-Thomas, Shari

2013

Overview

Adoptive T-cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) can induce tumor regression in up to 50% or more of patients with unresectable metastatic melanoma. However, current methods to expand melanoma TIL, especially the \"rapid expansion protocol\" (REP) were not designed to enhance the generation of optimal effector-memory CD8(+) T cells for infusion. One approach to this problem is to manipulate specific co-stimulatory signaling pathways to enhance CD8(+) effector-memory T-cell expansion. In this study, we determined the effects of activating the TNF-R family member 4-1BB/CD137, specifically induced in activated CD8(+) T cells, on the yield, phenotype, and functional activity of expanded CD8(+) T cells during the REP. We found that CD8(+) TIL up-regulate 4-1BB expression early during the REP after initial TCR stimulation, but neither the PBMC feeder cells in the REP or the activated TIL expressed 4-1BB ligand. However, addition of an exogenous agonistic anti-4-1BB IgG4 (BMS 663513) to the REP significantly enhanced the frequency and total yield of CD8(+) T cells as well as their maintenance of CD28 and increased their anti-tumor CTL activity. Gene expression analysis found an increase in bcl-2 and survivin expression induced by 4-1BB that was associated with an enhanced survival capability of CD8(+) post-REP TIL when re-cultured in the absence or presence of cytokines. Our findings suggest that adding an agonistic anti-4-1BB antibody during the time of TIL REP initiation produces a CD8(+) T cell population capable of improved effector function and survival. This may greatly improve TIL persistence and anti-tumor activity in vivo after adoptive transfer into patients.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adoptive transfer / Anticancer properties / Antigens / Antitumor agents / Apoptosis / Bcl-2 protein / Biology / Cancer therapies / CD137 antigen / CD28 antigen / CD28 Antigens - genetics / CD28 Antigens - immunology / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - transplantation / Cell Proliferation - drug effects / Cell survival / Cell Survival - drug effects / Cytokines / Cytotoxicity / Effector cells / Expansion / Gene expression / Gene Expression - drug effects / Humans / Immunoglobulin G / Immunoglobulin G - pharmacology / Immunologic Memory - drug effects / Immunological memory / Immunology / Immunotherapy / Immunotherapy, Adoptive / Inhibitor of Apoptosis Proteins - genetics / Inhibitor of Apoptosis Proteins - immunology / Lymphocyte Activation - drug effects / Lymphocytes / Lymphocytes T / Lymphocytes, Tumor-Infiltrating - drug effects / Lymphocytes, Tumor-Infiltrating - immunology / Lymphocytes, Tumor-Infiltrating - transplantation / Medicine / Melanoma / Melanoma - genetics / Melanoma - immunology / Melanoma - pathology / Melanoma - therapy / Memory cells / Metastases / Metastasis / Oncology / Patients / Peripheral blood mononuclear cells / Proto-Oncogene Proteins c-bcl-2 - genetics / Proto-Oncogene Proteins c-bcl-2 - immunology / Regression analysis / Science / Signal Transduction - drug effects / Signaling / Skin Neoplasms - genetics / Skin Neoplasms - immunology / Skin Neoplasms - pathology / Skin Neoplasms - therapy / Stem cells / Stimulation / Survival / Survivin / T cell receptors / T-cell receptor / Therapy / Tumor Cells, Cultured / Tumor necrosis factor / Tumor Necrosis Factor Receptor Superfamily, Member 9 - agonists / Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics / Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology / Tumor-infiltrating lymphocytes / Tumors