Table 2.
Advantages, limitations, and potential strategies improving CAR-T, CAR-NK and CAR-M therapy
| CAR-T cells | CAR-NK cells | CAR-M cells | |
|---|---|---|---|
| Advantages |
- Sufficient number of circulating T cells - Previous studies on hematological malignancies facilitating its use on solid tumors |
- Natural ability against non-self-cells - Direct and indirect killing functions due respectively to CAR and ADCC - Self-identification of normal cells by KIR - Reduced risk of CRS, ICANS and GvHD - Can be generated from different sources |
- M1 macrophages feature a pro-inflammatory phenotype - Antitumor activity by phagocytosis, presenting tumor antigen to Th1 cells and production of anti-inflammatory factors - Most abundant population in the TME of many cancer types - Important source of matrix metalloproteinase (MMP) which degrades almost all ECM - Can be generated from different sources |
| Limitations |
- Tumor antigen heterogeneity and tumor antigens loss - Difficulty in infiltrating tumors - Limited survival and persistence in the immunosuppressive tumor microenvironment - CRS, OTOT toxicity, neurotoxicity and GvHD |
- Limited tumor infiltration - Limited efficacy in CAR transduction - Limited survival and persistence in the immunosuppressive tumor microenvironment |
- Limited efficacy in CAR transduction - CRS toxicity - OTOT toxicity - Need differentiation to M1 phenotype |
| Strategies |
➣ Overcoming tumor antigen heterogeneity and tumor antigen loss: - Bispecific-CAR-T cells - Pooled CAR-T cells - Switch on or off CAR-T cells - AI (radiomics) ➣ Facilitating CAR-T cell tumor infiltration: - Nanobody-based CAR-T cell therapy - Chemokine receptor-expressing CAR-T cells - CAR-T cells local administration: intraperitoneal, intra-tumoral injection, porous microneedle patch - CAR-T cells targeting stromal cell-associated antigens - Matrix-degrading enzymes-secreting CAR-T cells - Molecular torpedo - Modifying CARs design, e.g., Hinge domain, transmembrane domain and co-stimulatory signaling - Alternative non-LV or RV transduction and in vivo delivery of CARs - CAR-T cells combination with ICIs (anti-CTLA-4 or anti-PD-1 monoclonal antibodies) - PD-1/CTLA-4- antibodies secreting CAR-T cells ➣ Overcoming the immunosuppressive tumor microenvironment and persistence: - CAR-T cells secreting immunostimulatory factors such as IL12, IL18, and IL15 - CAR-T cells targeting Treg, MDSCs and M2 macrophages - Combining CAR-T cells with chemotherapy ➣ Overcoming CAR-T cells’ CRS toxicity: - IL-1R antagonists-secreting CAR-T - IL-6 blockade - Neutralizing GM administration - CAR construct improvement - Control of CAR activity and survival in vivo |
➣ Improving the trafficking to the tumor site: - CAR-NK expressing chemokine receptors ➣ Improving the transduction efficiency of NK cells: - Retronectin, ectofusin-1 used as transduction enhancer - Baboon envelope pseudotyped lentivirus (BaEV-LV) - Electroporation and transposons for non-viral transduction ➣ Improving CAR-NK cytotoxicity: - Armored CAR-NK with co-stimulatory domains (DAP-10, DAP-12 or 2B4) - Combining CAR-NK with tyrosine kinase inhibitors - Combining CAR-NK with immune checkpoints inhibitors (anti-PD-1 antibodies) ➣ Improving in vivo survival and persistence within the TME: - Engineered CAR-NK to co-express stimulatory cytokine - Designed chimeric co-stimulatory converting receptor (CCCR)-NK for switching the immunosuppressive negative signal to an activating one - Combining CAR-NK cells with chemotherapy and radiotherapy ➣ Improving NK cell generation: - Using different sources of NK cells including NK92 cell line, iPSCs, hESC. |
➣ Improving the bioengineering of CAR-M: - Use of modified lentiviral virions containing Vpx - Use of adenovirus 5-fiber 35 vector (Ad5f35) for efficient gene transfer - Mannose-conjugated polyethyleneimine (MPEI) for effective gene delivery ➣ Enhancing the antitumor activity of CAR-M: - M2 to an M1 phenotype polarization - CAR iMAC ➣ Enhancing trafficking and persistence within the immunosuppressive TME: - CAR-CD147 construct - CCL19-expressing CAR-macrophages - Combination therapy with anti-CD47, anti-CD20 and anti-TAA antibodies |