Navigating CAR-T cells through the solid-tumour microenvironment

Abstract

The adoptive transfer of T cells that are engineered to express chimeric antigen receptors (CARs) has shown remarkable success in treating B-cell malignancies but only limited efficacy against other cancer types, especially solid tumours. Compared with haematological diseases, solid tumours present a unique set of challenges, including a lack of robustly expressed, tumour exclusive antigen targets as well as highly immunosuppressive and metabolically challenging tumour microenvironments, that limit treatment safety and efficacy. Here, we review protein-and cell-engineering strategies that seek to overcome these obstacles and produce next-generation T cells with enhanced tumour-specificity and sustained effector function for the treatment of solid malignancies.T-cell targeting of other TAAs has similarly led to undesired but clinically tractable adverse events. Melanoma antigen recognized by T cells 1 (MART-1) and glycoprotein 100 (gp100) are TAAs expressed not only in melanomas but also in healthy melanocytes in the skin, eyes, and ears 12 .Patients with metastatic melanoma who received T cells engineered to express TCRs specific for MART-1 or gp100 experienced transient melanocyte toxicity, resulting in damages to skin, eyes, or ears that were treatable with steroid applications 12 . Notably, a subset of patients experienced melanocyte toxic effects without appreciable tumour clearance 12 , indicating that on-target, offtumour toxicities can happen even in the absence of robust anti-tumour response. Patients with metastatic colorectal cancer who received T cells expressing carcinoembryonic antigen (CEA)targeted TCRs experienced severe transient colitis due to CEA expression on healthy epithelial cells in the gastrointestinal tract, with limited anti-tumour responses 13 . Similarly, treatment with carboxy-anhydrase-IX (CAIX) CAR-T cells in patients with metastatic renal carcinoma resulted in dose-limiting toxicity to the liver and bile-duct epithelial cells despite being a first-generation CAR, which is expected to provide limited tumour-killing efficacy 14 . These cases highlight the delicate balance between eliciting potent anti-tumour activities with preventing severe off-target toxic effects.In certain clinical studies, unanticipated off-target toxic effects have resulted in life-threatening complications. Melanoma associated antigens (MAGE) are cancer-testes antigens (CTAs) that are absent from healthy adult tissue but overexpressed in a variety of cancers 15 . However, three out of nine patients treated with MAGE-A3-targeted TCR-T cells experienced severe neurotoxicity, resulting in two fatalities 15 . This was attributed to cross-reactivity of the MAGE-A3 TCR to unanticipated MAGE-A12 expression in the brain 15 . In a separate MAGE-A3 TCR study, two patients experienced lethal cardiac toxicity due to myocardial damage induced by TCR crossreactivity with the protein titin, which is found in myocardium 16,17 . It should be noted that the tested MAGE-A3 TCRs were avidity-and affinity-enhanced with the intenti...

PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

“…Thus, the same configuration should be considered when similar results are seen in future investigations of PTK7-CAR T-cell's toxicity profiles; alternatively, tuning scFv affinity and/or concomitantly integrating different co-stimulatory domains may ameliorate the potential concern of on-target off-tumor effect as typical representation for CAR T-cell therapy targeting a range of different antigens including but not limited to HER2, EGFR, CD38 (8,51,52). Given the above inherent risks, multiple inducible safety controls that can be built into or applied in conjunction with CAR-T cells should be considered, such as inducible caspase 9 (iCasp9) or tEGFR tag as we integrated in CAR design where tEGFR-expressing CAR-T can be depleted by commercially available antibody cetuximab in case of emergent side effects (53). In sum, further thorough investigations are definitely needed to fully explore the potential toxicities of PTK7-CAR T cells before translating into clinic by using PTK7-CARs with cross-reactivity in mouse and even non-human primate models.…”

Chimeric Antigen Receptor T-Cell Therapy: The Light of Day for Osteosarcoma

“…Because of their high targeting and powerful antitumor activity, CAR-T cells are widely used in research and the treatment of various cancers. Recently, researchers have also extended CAR-T therapy to solid tumors, including OS [20][21][22]. Furthermore, related studies have reported that adoptively transferred effector cells derived from naive T cells mediate superior antitumor effects, and youth carry more naive cells [124,125].…”

“…Based on these encouraging results, the Food and Drug Administration (FDA) recently approved two CAR-T cells targeting the CD19 protein for the treatment of acute lymphoblastic leukemia and diffuse large B-cell lymphoma [19]. Recently, researchers have also extended CAR-T therapy to solid tumors, including OS [20][21][22]. Koksal et al summarized CAR-T-cell therapy for OS several years ago [22].…”

Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment

“…Next, we evaluated the delivery of engineered T cells in our model. Chimeric antigen receptor (CAR) T cells have been heavily investigated in treating solid tumors in recent years [50]. CAR T cells have to arrest on and penetrate through the endothelium, which negatively regulate T cell functions [51], before reaching the cancer cells expressing the tumor (associated) antigens.…”