CAR-T cells: the long and winding road to solid tumors

Abstract

Adoptive cell therapy of solid tumors with reprogrammed T cells can be considered the “next generation” of cancer hallmarks. CAR-T cells fail to be as effective as in liquid tumors for the inability to reach and survive in the microenvironment surrounding the neoplastic foci. The intricate net of cross-interactions occurring between tumor components, stromal and immune cells leads to an ineffective anergic status favoring the evasion from the host’s defenses. Our goal is hereby to trace the road imposed by solid tumors to CAR-T cells, highlighting pitfalls and strategies to be developed and refined to possibly overcome these hurdles.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Adoptive transfer of engineered T cells is an effective treatment for certain hematological malignancies [152] but it faces many challenges when targeting solid tumors [153,154]. A large number of CAR clinical sutides are attempting to replicate the success of α-CD19 and α-BCMA CARs against the solid neoplasms, but the preliminary outcome of more than 100 trials are less encouraging.…”

Preservation of cell-based immunotherapies for clinical trials

“…Other B-cell antigens, such as CD20, CD22 and k light chain, have also been targeted in clinical studies for the treatment of different types of lymphoma and leukemia, and studies using CAR T cells targeting B-cell maturation antigen have revealed very promising clinical outcomes for the treatment of multiple myeloma [26]. In addition to hematologic cancers, T cells have also been genetically modified to target antigens of solid tumors, such as prostate cancer [27] and malignant pleural mesothelioma [28,29], although the successful development of CAR T-cell therapy for solid tumors has its unique challenges [25]. HSA, human serum albumin; LN, liquid nitrogen.…”

“…Two immunotherapies based on CD19-targeted CAR T cells have been approved by the Food and Drug Administration to treat two types of hematologic cancers: acute lymphoblastic leukemia (KYMRIAH) and diffuse large B-cell lymphoma (YESCARTA and KYMRIAH) [25]. Other B-cell antigens, such as CD20, CD22 and k light chain, have also been targeted in clinical studies for the treatment of different types of lymphoma and leukemia, and studies using CAR T cells targeting B-cell maturation antigen have revealed very promising clinical outcomes for the treatment of multiple myeloma [26].…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…extracellular matrix), chronic inflammation and the presence of immunosuppressive molecules and immune cells. Furthermore, high tumor heterogeneity can facilitate antigen escape and in vivo CAR T cells expansion is significantly less pronounced than in patients with hematologic malignancies (103,104). In order to prevent potentially lethal toxicities, safety switch strategies are being tested (98) and the University of Pennsylvania group demonstrated the feasibility, although with limited efficacy, of administering mRNA electroporated mesothelin-specific CAR T cells in pancreatic adenocarcinoma patients (105).…”