Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells

Abstract

The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR) modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B cell non-Hodgkin lymphoma (B-NHL). Early phase clinical trials are presently assessing CAR T cell safety and efficacy in additional malignancies. Herein, we discuss clinical results from the largest series to date investigating CD19-targeted CAR T cells in B-ALL, CLL, and B-NHL, including discussion of differences in CAR T cell design and production and treatment approach, as well as clinical efficacy, nature of severe cytokine release syndrome and neurologic toxicities, and CAR T cell expansion and persistence. We additionally review the current and forthcoming use of CAR T cells in multiple myeloma and several solid tumors, and highlight challenges and opportunities afforded by the current state of CAR T cell therapies, including strategies to overcome inhibitory aspects of the tumor microenvironment and enhance antitumor efficacy.

Complement C3-dependent uptake of targeted liposomes into human macrophages, B cells, dendritic cells, neutrophils, and MDSCs

“…1,18 Strategies for promoting an antitumor immune response would benefit from a nanoparticle system that can target these cells, all of which display the receptor for complement C3. 3,9,19 Liposomes were therefore formulated with a lipid-attached OPSS group, which can form a disulfide bond with activated complement C3. After binding complement, we show that these liposomes are taken up by human macrophages, M-MDSCs, G-MDSCs, neutrophils, dendritic cells, and B cells.…”

“…1,3 APCs present 26,27 Techniques to improve antigen presentation include ex vivo strategies such as adoptive T-cell transfer and in vivo strategies such as nanoparticle antigen delivery. 8,9,19,28 Drawbacks of ex vivo techniques include high cost and lack of a memory T-cell population after inoculation into the patient. 29,30 Nanoparticle delivery systems have had some success, but often they are targeted only to macrophages and dendritic cells, and most targeted systems require costly antibodies or peptides that are difficult to store and scale up to pharmaceutical quantities.…”

PSCA and MUC1 in non-small-cell lung cancer as targets of chimeric antigen receptor T cells

“…[14][15][16] However, the broad applicability of these cells for solid cancer is limited by the paucity of truly tumor-specific target antigens. Additionally, the heterogeneity of tumor-associated antigens (TAAs) in solid cancers complicates CAR T cell therapies, as the targets may differ among various cancers and even patients of a same cancer.…”

Antibody darts on target for acute myelogenous leukemia

“…Antibodies have been used alone, but can be engineered linking them to toxins or to T lymphocytes, either joined to the zeta chain of the T cell receptor (chimeric antigen receptors), or through bi-specific antibodies binding T cells by anti CD3 to the lymphoid target through, for example the anti CD19 variable portion [reviewed in (1)]. Clinical trials clearly confirm the power of strategies which bring T cells with their cytotoxic potency into close proximity with surface antigen targets on the malignant cell (2)(3)(4).…”