Effector memory and central memory NY-ESO-1-specific re-directed T cells for treatment of multiple myeloma

Abstract

The cancer-testis antigen NY-ESO-1 is a potential target antigen for immune therapy expressed in a subset of patients with multiple myeloma. We generated chimeric antigen receptors (CARs) recognizing the immunodominant NY-ESO-1 peptide 157-165 in the context of HLA-A*02:01 to re-direct autologous CD8(+) T cells towards NY-ESO-1(+) myeloma cells. These re-directed T cells specifically lysed NY-ESO-1(157-165)/HLA-A*02:01-positive cells and secreted IFNγ. A total of 40% of CCR7(-) re-directed T cells had an effector memory phenotype and 5% a central memory phenotype. Based on CCR7 cell sorting, effector and memory CAR-positive T cells were separated and CCR7(+) memory cells demonstrated after antigen-specific re-stimulation downregulation of CCR7 as sign of differentiation towards effector cells accompanied by an increased secretion of memory signature cytokines such as IL-2. To evaluate NY-ESO-1 as potential target antigen, we screened 78 bone marrow biopsies of multiple myeloma patients where NY-ESO-1 protein was found to be expressed by immunohistochemistry in 9.7% of samples. Adoptively transferred NY-ESO-1-specific re-directed T cells protected mice against challenge with endogenously NY-ESO-1-positive myeloma cells in a xenograft model. In conclusion, re-directed effector- and central memory T cells specifically recognized NY-ESO-1(157-165)/ HLA-A*02:01-positive cells resulting in antigen-specific functionality in vitro and in vivo.

The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy

“…4,8 In myeloma, a multitude of studies have investigated MM-associated antigens, yielding a handful of promising targets. [25][26][27][28][29][30][31][32][33][34][35] However, these studies were limited in scope of antigens and HLA allotypes. 42 In our previous studies in acute myeloid leukemia and chronic lymphocytic leukemia, we demonstrated that the comprehensive and comparative analysis of the HLA-presented antigenome can identify extensive panels of broadly presented T-cell epitopes covering a multitude of HLA allotypes.…”

“…24 An array of myeloma-associated T-cell antigens has been described in previous studies. [25][26][27][28][29][30][31][32][33][34][35] Most of these antigens were identified based on gene expression analysis and reverse immunology. Some of these antigens (WT1, 36,37 RHAMM, 38,39 hTERT, 40 and Survivin 40,41 ) have already found their way into clinical trials, showing promising results in terms of induction of specific T-cell responses as well as clinical responses in single patients.…”

Engineered cytotoxic T lymphocytes with AFP-specific TCR gene for adoptive immunotherapy in hepatocellular carcinoma

“…In 1999, the first successful study had demonstrated that transfer of an HLA-A2-restricted MART-1 antigen-specific TCR into human T cells could confer them the specificity toward malignant melanomas [14]. Several preclinical and clinical studies have also exhibited that genetic modification with a tumor antigen-specific TCR could yield an antigen-specific T cell population [15][16][17][18][19][20][21].…”

T cells targeting NY-ESO-1 demonstrate efficacy against disseminated neuroblastoma

“…Novel therapies like bi-specific antibodies are demonstrating early clinical success, 27,28 and methods that bypass the endogenous immune system, such as genetically-engineered T cells, have also drawn a great deal of attention for the successes demonstrated using chimeric antigen receptors. 2,8,9,29 While several adult cancer have been evaluated for NY-ESO-1 expression and its ability to serve as an immunotherapeutic target, 15,16,30 pediatric cancers have been largely overlooked. A trial targeting NY-ESO-1 C synovial cell carcinoma using the T cells investigated in this report is currently enrolling; however, this clinical trial is, to our knowledge, the only such pediatric trial targeting NY-ESO-1 (Clinicaltrials.gov Identifier NCT01343043).…”