Adoptive cellular therapy, in which immune cells are selected or engineered to direct specificity toward diseased cells, has recently proved efficacious in some cancers, particularly including several of the hematologic malignancies. These therapies include tumor-infiltrating lymphocytes, T-cell receptor transgenic cells, and chimeric antigen receptor (CAR) T cells, with the latter being the most advanced for the treatment of hematologic malignancies. To produce CAR T cells, T lymphocytes are engineered to express synthetic immune signaling molecules, which fuse the specificity of an anti-tumor monoclonal antibody with the potent cytotoxic and immunosurveillance functions of T cells. In clinical studies, CAR T cells have engendered deep and long-lasting remissions in children and young adults with resistant and relapsed acute lymphoblastic leukemia and in adults with diffuse large B-cell lymphoma, with further promising data in myeloma. Although CAR T-cell therapy has the potential to transform cancer treatment as part of the “personalized medicine” revolution, important obstacles remain to be overcome. These include identification of further tumor-specific targets, enhancement of efficacy while reducing toxicity and cost, and increasing patient access.
Acronyms and Abbreviations
ACT, adoptive cellular therapy; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia ; BCMA, B-cell maturation antigen ; CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CNS, central nervous system; CR, complete response; CRi, complete response with incomplete hematological recovery; CRS, cytokine release syndrome; DLBCL, diffuse large B-cell lymphoma; DLI, donor lymphocyte infusion; DMSO, dimethyl sulfoxide; EBV, Epstein Barr virus; GvHD, graft versus host disease; HIV, human immunodeficiency virus; HL, Hodgkin lymphoma; HLA, human leucocyte antigen; HSC, hematopoietic stem cell; HSCT, hemopoietic stem cell transplantation; ICANS, immune cell-associated neuropathy syndrome; IL, interleukin; ITT, intention to treat; OS, overall survival; PBMCs, peripheral blood mononuclear cells; PD-L1, programmed death-ligand 1; PD-L2, programmed death-ligand 2; PFS, progression free survival; PMBCL, primary mediastinal large B-cell lymphoma; scFv, single-chain variable fragment; TALENs, transcription activator-like effector nucleases; tanCAR, tandem-CAR; TILs, tumor infiltrating lymphocytes; TGF, transforming growth factor; WT-1, Wilms tumor protein.
In the 21st century, immunotherapy has emerged as a new cornerstone of cancer treatment, harnessing the ability of the immune system to detect and control cancer. Therapies including monoclonal antibodies, immune checkpoint inhibitors, bispecific T-cell engagers, and others have now entered routine clinical practice, revolutionizing the treatment of many malignancies. Adoptive cellular therapies (ACT), of which anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is the most prominent example, constitute a novel and powerful type of immunotherapy. ACT is a process where immune effector cells are harvested from a patient or donor, selected or engineered ex vivo to enhance anti-tumor functionality, and infused into the patient. The principle is simple yet profound: prime or engineer a patient’s immune cells to recognize the patient’s cancer, bypass its defences, and destroy it. Potent efficacy has been demonstrated in a number of hematologic malignancies, but important barriers must be overcome before these therapies have an optimal therapeutic profile and can become more widely used.