T-Cell Therapy Using Interleukin-21–Primed Cytotoxic T-Cell Lymphocytes Combined With Cytotoxic T-Cell Lymphocyte Antigen-4 Blockade Results in Long-Term Cell Persistence and Durable Tumor Regression

Abstract

Purpose Peripheral blood-derived antigen-specific cytotoxic T cells (CTLs) provide a readily available source of effector cells that can be administered with minimal toxicity in an outpatient setting. In metastatic melanoma, this approach results in measurable albeit modest clinical responses in patients resistant to conventional therapy. We reasoned that concurrent cytotoxic T-cell lymphocyte antigen-4 (CTLA-4) checkpoint blockade might enhance the antitumor activity of adoptively transferred CTLs. Patients and Methods Autologous MART1-specific CTLs were generated by priming with peptide-pulsed dendritic cells in the presence of interleukin-21 and enriched by peptide-major histocompatibility complex multimer-guided cell sorting. This expeditiously yielded polyclonal CTL lines uniformly expressing markers associated with an enhanced survival potential. In this first-in-human strategy, 10 patients with stage IV melanoma received the MART1-specific CTLs followed by a standard course of anti-CTLA-4 (ipilimumab). Results The toxicity profile of the combined treatment was comparable to that of ipilimumab monotherapy. Evaluation of best responses at 12 weeks yielded two continuous complete remissions, one partial response (PR) using RECIST criteria (two PRs using immune-related response criteria), and three instances of stable disease. Infused CTLs persisted with frequencies up to 2.9% of CD8 T cells for as long as the patients were monitored (up to 40 weeks). In patients who experienced complete remissions, PRs, or stable disease, the persisting CTLs acquired phenotypic and functional characteristics of long-lived memory cells. Moreover, these patients also developed responses to nontargeted tumor antigens (epitope spreading). Conclusion We demonstrate that combining antigen-specific CTLs with CTLA-4 blockade is safe and produces durable clinical responses, likely reflecting both enhanced activity of transferred cells and improved recruitment of new responses, highlighting the promise of this strategy.

Is autoimmunity the Achilles' heel of cancer immunotherapy?

“…3) shared by normal tissue, which thereby leads to loss of tolerance and autoimmunity. ES has been documented in patients receiving tumor vaccines 41 and in patients who have undergone adoptive transfer (Box 1) of CTLs and CAR T cells 42,43 . Checkpoint therapy with ipilimumab can induce ES 44 , and it is likely that neoantigen-directed immune responses against tumors, when followed by ES, can trigger autoimmunity against nonmalignant tissues in which the neoantigens are absent.…”

Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

“…Given the increased activity of A 2A R -/-CAR T cells and our in vitro data with CAR T cells expressing shRNAs targeting the A 2A R, we propose that strategies designed to target A 2A R at the genetic level are of interest and may be the subject of further studies. Furthermore, given that our data indicate that the A 2A R pathway limits the activity of patient-derived CAR T cells and the emergence and success of clinical trials combining adoptive cell transfer (ACT) with both anti-CTLA-4 (59,60) and anti-PD-1 (NCT02652455), we believe that clinical trials combining CAR T cells and A 2A R blockade are warranted.…”

Future perspectives in melanoma research

“…Endogenous population of tumor reactive T cell infiltrate is often absent in many solid tumor malignancies and transfer of such T cells to patients may lead to improved therapy. The augmentation of endogenous immune response may be obtained through autologous tumor-infiltrating lymphocytes (TILs), engineered T cells such as T cell receptor (TCR) modified T cells or chimeric antigen modified T cells (CAR), or circulating T cell therapy [28, 29]. Endogenous T cells (ETC) are derived from peripheral blood or tumor infiltrating lymphocytes as a source of effector cells for adoptive cell therapy.…”

“…Preparation time can be significantly reduced by using clinical grade peptide-MHC-multimer-based sorting of antigen specific T cells. Strategies to enhance in vivo persistence of transferred T cells can lead to improved antitumor efficacy [28, 30–32]. However, the extrinsic (patient conditioning) and intrinsic factors (effector cells) contributing to long-term in vivo persistence are not well-defined.…”

“…CTL clones in the infusion product were characterized by an effector memory phenotype and CTL that persisted long term acquired phenotypic and/or functional qualities of central memory type CTLs in vivo [28, 33]. …”