Cellular Immunotherapy in B-Cell Malignancy

Abstract

In recent years, cellular immunotherapy in B-cell malignancies has been driven by adoptive transfer of genetically engineered T cells expressing chimeric antigen receptors (CARs). CARs consist of a single chain variable fragment (scFv) of a monoclonal antibody, a spacer domain, a transmembrane domain, an intracellular signaling domain, and additional costimulatory domains. The bulk of clinical data available is on CD19-targeting CAR T cells for the treatment of B-cell acute lymphocytic leukemia (B-ALL), chronic lymphocytic leukemia, and B-cell non-Hodgkin lymphoma. Results so far have been promising with impressive rates and depth of remission especially among B-ALL patients. However, CAR T-cell therapy is a complex multi-step process, and clinical trials so far differ profoundly in CAR construct used, gene transfer method, composition of the cellular product, lymphodepletion, and CAR T-cell dose used. Randomized trials will be needed to conclusively evaluate the implications of these differences. The treatment concept is associated with significant neurotoxicity and potentially lethal cytokine release syndrome, both of which require specific management. Improvements in CAR design may help to overcome toxicity, the effects of an immunosuppressive microenvironment, and tumor escape by development of antigen-negative clones. This review will explain the mechanism of action, summarize the clinical experience with this treatment modality so far, and explore future developments in the field.

BCMA peptide-engineered nanoparticles enhance induction and function of antigen-specific CD8+ cytotoxic T lymphocytes against multiple myeloma: clinical applications

“…21,22 In addition, unlike commonly used treatments or CAR-T therapy which can induce significant toxicities in patients, vaccines induce endogenous immune responses and TAA-specific memory function with few adverse events. [23][24][25] With this rationale, we and others have developed methods to improve immune and clinical response to cancer vaccines. Specifically, we are continuously identifying TAA uniquely expressed on CD138 + tumor cells from newly diagnosed MM patients (N=1,254) and are developing protocols to target the novel antigens, as individually or as a multipeptide cocktail.…”

Novel CD19-targeted TriKE restores NK cell function and proliferative capacity in CLL

“…AlloHCT and CAR19 T-cell approaches have both shown promise in CLL and conceptually demonstrated curative effects of cellular therapy; however, both are highly complex individualized procedures that can be associated with substantial morbidity and mortality. 35 In addition, their application is restricted to patients without major comorbidities and is limited by autologous CAR T-cell exhaustion and toxicities. 7,36 By triggering an endogenous NK cell response, which displays a less toxic profile than T-cell responses, 161519 TriKE offers a potentially valuable off-the-shelf alternative to CAR T-cell therapies that could be used alone or in combination with adoptive NK cell therapy.…”

New targets for therapy: antigen identification in adults with B-cell acute lymphoblastic leukaemia

“…BiTEs conjugate two mAbs recognizing leukaemic cells and cytotoxic T lymphocytes (CTLs), a CD3-and a CD19-binding part, and direct CTLs against malignant B cells. Blinatumomab was the first-approved BiTE to be used to treat ALL [7,11,12]. Phase I/II and phase III trials conducted with blinatumomab described better results for patients in terms of complete remission, minimal residual disease responses, response rates and survival [9].…”