Hunting for clinical translation with innate-like immune cells and their receptors

Abstract

Allogeneic stem cell transplantation (allo-SCT) has so far been the most effective immunotherapy for hematological malignancies. However, it is becoming increasingly clear that the immunotherapeutic concepts underlying allo-SCT as well as the traditional dissection of the immune system into innate and adaptive arms need substantial refinement. More and more cell types migrate into the interface between innate and adaptive immunity, creating new terms such as innate-like lymphocytes. These innate-like cells, which include natural killer (NK) cells and γδT cells, could provide unique advantages to therapeutic interventions aimed at treating hematological malignancies, including protection against tumor relapse and viral infections without causing harmful graft-versus-host disease (GVHD). Recent molecular and conceptual insights into these subpopulations have opened new avenues to exploit their exciting features for the development of new compounds and to revisit current therapeutic standards in the treatment of hematological cancers. This review therefore aims to discuss the rapid progress in the understanding of molecular mechanisms by which NK cells and γδT cells recognize malignancies and viral infections, and the value of this increasing knowledge to complement the battle against life-threatening complications of current strategies to treat cancer.

Cell-Cell Communication in the Tumor Microenvironment, Carcinogenesis, and Anticancer Treatment

“…HSC also function as antigen-presenting cells (APCs) by stimulating the proliferation of natural killer T-cells (NKT cells) [149]. NKT cells string together characteristics of innate and adaptive immunity [150], reviewed in [151]: they activate receptors and express inhibiting receptors that sense the presence of the MHC class I molecules expressed on all healthy cells [152], reviewed in [151]. Cx43 regulates NKT activation: knockdown reduced CD69 and CD25 expression and also the IFN-γ secretion usually released by NKT induced through human dendritic cells and blocking the Cx43-suppressed NKT-mediated tumor cell lysis [153].…”

Untouched GMP-Ready Purified Engineered Immune Cells to Treat Cancer

“…By utilizing a novel tumor-specific immune receptor naturally interfering with endogenous abTCR chains (27)(28)(29)(30), an optimized expression system, and clinical grade anti-abTCR beads, we developed a highly pure engineered cellular product with improved antitumor activity. The production process can be readily translated to meet GMP-grade standards and the resulting cellular medicine can be applied as part of an immune intervention strategy in a broad population of cancer patients in autologous, allogeneic, and third-party situations.…”

“…A subset of gdT cells express a TCR composed of Vg9 and Vd2 chains that sense accumulated nonpeptidic pyrophosphate molecules (phosphoantigens), intermediates of a deregulated mevalonate pathway of isoprenoid synthesis, via BTN3A1 (CD277) and reported by us (27)(28)(29) and others (32) to display potent cytotoxicity against a broad range of tumor species. Other intriguing properties of gdTCRs are the absence of forming potentially self-reactive mixed TCR dimers, their HLA-independency, absence of immunogenicity, which can either result in reduced therapeutic efficacy or substantial toxicity and avoidance of education and long-term tolerance when expressing innate immune receptors out of the context of an innate immune cell (30,31).…”

Sufficient Immunosuppression with Thymoglobulin Is Essential for a Successful Haplo-Myeloid Bridge in Haploidentical-Cord Blood Transplantation

“…It was hypothesized that by using this depletion method, the haplo-innate cells (NK and gamma-delta T cells) are coinfused, which may have an additional antileukemic effect in the early phase after transplantation [20,21]. No ATG was given in this protocol to preserve the innate cells after transplantation.…”