A Potent Vaccination Strategy That Circumvents Lymphodepletion for Effective Antitumor Adoptive T-cell Therapy

Abstract

Adoptive cell therapy (ACT) using tumor-reactive T lymphocytes is a promising approach for treating advanced cancer. Successful tumor eradication depends primarily on the expansion and survival of the adoptively transferred T cells. Lymphodepletion using total body irradiation (TBI) and administering high dose IL2 have been used with ACT to promote T cell expansion and survival to achieve maximal therapeutic effects. However, TBI and high dose IL2 increase the risk for major complications that impact overall survival. Here we describe an alternative approach to TBI and high dose IL2 for optimizing ACT, resulting in dramatic therapeutic effects against established melanomas in mice. Administration of a potent, non-infectious peptide vaccine after ACT dramatically increased antigen-specific T cell numbers leading to enhancement in the survival of melanoma-bearing mice. Furthermore, combinations of peptide vaccination with PD1 blockade or IL2/anti-IL2 antibody complexes led to complete disease eradication and long-term survival in mice with large tumors receiving ACT. Our results indicate that PD1 blockade and IL2/anti-IL2 complexes enhance both the quantitative and qualitative aspects of the T cell responses induced by peptide vaccination after ACT. These findings could be useful for the optimization of ACT in cancer patients without the need of toxic adjunct procedures.

Effective Cooperation of Monoclonal Antibody and Peptide Vaccine for the Treatment of Mouse Melanoma

“…We and other investigators showed that the need for lymphodepletion, which causes major complications, can be avoided by using peptide vaccines that strongly activate adoptively transferred T cells in vivo (25,42). The novelty of the current study lies in the fact that the endogenous T cell repertoire is exploited in combination with passive injections of the anti-TRP-1 mAb TA99.…”

Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion

“…Overall, our study confirmed previous findings that lymphopenia is not a prerequisite for effective ACT (46). Several other approaches to improve ACT outcomes in the absence of irradiation and chemotherapy have been recently explored, including the use of antibodies for specific cell type depletion (46), genetically engineered tumor-specific T cells (47), Toll-like receptor (TLR) ligands (48) and other γ-chain cytokines (46,49). One foreseeable advantage of the regimen proposed in this study is the absence of CD4 + T cell ablation.…”

Interleukin-2: Biology, Design and Application

“…Given these properties, IL-2/S4B6 complexes could be used therapeutically in metastatic malignancies and chronic viral infection. In support of this notion, several groups have reported favorable results using IL-2/S4B6 complexes either as a monotherapy or in combination with another agent (such as Toll-like receptor ligand, agonist anti-OX40 mAb, or peptide vaccine) in various cancer models, including B16 melanoma, Lewis lung carcinoma, MC38 colon carcinoma, MCA-205 sarcoma, and TRAMP-C1 prostate carcinoma [31,[48][49][50][51][52][53]. Moreover, IL-2/S4B6 complexes have shown efficacy in models of acute and chronic infection [54,55].…”