Adoptive T-cell therapy for hematological malignancies using T cells gene-modified to express tumor antigen-specific receptors

Abstract

The functional properties of the adoptive immune response mediated by effector T lymphocytes are decisively regulated by their T-cell receptors (TCRs). Transfer of genes encoding target antigen-specific receptors enables polyclonal T cells to redirect toward cancer cells and virally infected cells expressing those defined antigens. Using this technology, a large population of redirected T cells displaying uniform therapeutic properties has been produced, powerfully advancing their clinical application as "cellular drugs" for adoptive immunotherapy against cancer. Clinically, anticancer adoptive immunotherapy using these genetically engineered T cells has an impressive and proven track record. Notable examples include the dramatic benefit of chimeric antigen receptor gene-modified T cells redirected towards B-cell lineage antigen CD19 in patients with chronic lymphocytic leukemia, and the impressive outcomes in the use of TCR gene-modified T cells redirected towards NY-ESO-1, a representative cancer-testis antigen, in patients with advanced melanoma and synovial cell sarcoma. In this review, we briefly overview the current status of this treatment option in the context of hematological malignancy, and discuss a number of challenges that still pose an obstacle to the full effectiveness of this strategy.

Boost and loss of immune responses against tumor-associated antigens in the course of pregnancy as a model for allogeneic immunotherapy

“…11, 39 The current study represents, to the best of our knowledge, the first comprehensive work to study the exact frequencies of T-lymphocyte responses against clinically relevant TAAs in a large group of healthy individuals. Here, we could show that one-third of volunteer donors do carry significant immune responses against at least 1 of the studied TAAs.…”

“…35,36 Consequently, several immunotherapeutic approaches nowadays focus on TAAs as target antigens to mount antileukemic immune responses in the absence of GVHD. 34,37 Although it is well accepted that TAA-specific immune responses play a central role in overall GVL, 10,[38][39][40] little is known about their origin and ability to persist as functionally active immune cells in the host preventing relapse.…”

“…11,[36][37][38][39][40][41][42] So far, the presence of these immune responses in healthy individuals could be only demonstrated in cohorts of limited size.…”

Current status of ex vivo gene therapy for hematological disorders: a review of clinical trials in Japan around the world

“…Particularly for congenital diseases, newly developed gene-editing technology, excellently reviewed by Voytas and Tolar in this special issue, will unquestionably change current gene therapy approaches using autologous HSCs [84]. In the case of malignancies, the recent development of gene-modified T-cell technologies, including chimeric antigen receptors and immune checkpoint inhibitors, will change the gene therapy modality for treatment of solid tumors as well as hematological malignancies [85,86].…”

An Empirical Study of the Prescription Pattern of Drugs for Hematological Malignancies in Japan from 2010–2014

“…In this way, more and more molecularly targeted drugs are being developed for cancer therapies around the world, including in Japan. 3) In addition, gene therapy [4][5][6][7] and immunotherapy [8][9][10][11] have been developed for hematological malignancies, suggesting that the number of the treatment options will increase in the near future.…”