The basics of CAR T design and challenges in immunotherapy of solid tumors — Ovarian cancer as a model

Abstract

Chimeric antigen receptor T cells are T cells genetically engineered with CAR constructs which mainly contain scFV and TCR zeta chain. With promising development in blood cancers, CAR T trials are also applied in solid cancers. However, the treatment effect in solid cancers is lower than expected. This review summarizes difference of CAR T applications in solid and blood cancers. Future challenges of CAR T cell treatment in solid cancer are also discussed using ovarian cancer as an example.

Neuroblastoma Origin and Therapeutic Targets for Immunotherapy

“…Later, researchers that developed the next generations of GD2-specific CAR T cells encountered difficulties and limitations that are typical for chimeric antigen receptor T cells targeting all types of solid tumors. Several of the most important limitations that hinder the development of CAR T therapies for solid tumors are as follows: Cell and antigen heterogeneity in solid tumors [ 262 ] On-target/off-tumor toxicity caused by expression of targets for CAR T cells on healthy body cells The inhibitory effect of the tumor microenvironment of solid tumors, and the limited ability of CAR T cells to penetrate solid tumors due to physical barriers from the surrounding stroma and infiltrating protumor immune cells, as well as absence of chemokine receptors [ 262 , 263 ], Suppression of T cell functional activity, which manifests itself in early T cell exhaustion due to tonic signaling, and activation-induced cell death (AICD) of CAR T cells upon interaction with the antigen [ 263 , 264 ] …”

“…The inhibitory effect of the tumor microenvironment of solid tumors, and the limited ability of CAR T cells to penetrate solid tumors due to physical barriers from the surrounding stroma and infiltrating protumor immune cells, as well as absence of chemokine receptors [ 262 , 263 ],…”

Epithelial Ovarian Cancer and the Immune System: Biology, Interactions, Challenges and Potential Advances for Immunotherapy

“…Other methods of nonviral gene transfer such as sleeping beauty transposon and clustered regularly interspaced short palindromic repeats (CRISPR) are being investigated [ 334 , 335 ]. CAR-T design has undergone several generational changes since they were first developed in 1989 [ 336 ]. See Figure 3 for the different generations of CAR designs.…”

“…Enhancements may include chemokine receptors and/or cytokine transgenes with inducible expression and release of their payload (e.g., IL-12 a cytokine with anti-tumour activity and important for the regulation of adaptive T-cell responses), a controllable on-off switch, or suicide gene [ 261 , 339 ]. Bispecific CARs can simultaneously target 2 antigens/epitopes [ 336 , 339 , 340 ].…”

“…In addition to the general immune and TME targets for therapy applicable to many cancer types as discussed in previous sections, a large number of different TAAs are expressed in ovarian cancer that have been targeted in clinical trials and shown in Table 3 . Apart from NY-ESO-1 and other CTA antigens, these include MUC16, mesothelin, and folate receptors [ 336 ], as well as antigens not widely expressed outside of the reproductive system (e.g., follicle-stimulating hormone receptor, FSHR) [ 362 ].…”