Table 1.

Innovative strategies in CAR T Cell Therapy.

	Strategy	Objective	Mechanism	Potential Outcomes
Synthetic Biology and Engineering	Multiplexed CARs 19, 20	Prevent tumor escape due to antigen loss or heterogeneity	Target multiple tumor-associated antigens to address antigen variability and loss	Enhanced tumor targeting and reduction in tumor escape mechanisms
	Modular/Universal CARs 21–26	Increase flexibility in targeting	Use of switchable, bispecific adaptors to redirect CAR T cells against various tumor antigens	Greater adaptability and precision in targeting tumors
	Synthetic Notch (SynNotch) CARs 27–29	Enhance specificity and safety of activation	Use dual antigen recognition strategy to initiate CAR transcription only after interacting with a primary antigen	More precise tumor targeting, reduced off-tumor activity, enhanced safety, and reduced potential toxicities
	Hybrid CARs 30–36	Enhance targeting of cancer-specific antigens and reduce tonic signaling	Combine TCR and CAR features to recognize intracellular antigens presented by MHC molecules at ultra-low densities	Broadened therapeutic applicability, ability to target the entire proteome of cancer cells
	Armored CAR T cells 39–41	Enhance efficacy and persistence	CAR T cells engineered to secrete cytokines or express pro-inflammatory ligands	Increased persistence and efficacy, and modulation of the TME
Manufacturing Advancements	CRISPR/Cas9 gene editing 42–44	Enhance CAR T cell functionality and persistence	Genetic modifications to secrete cytokines or express pro-inflammatory ligands	Improved anti-tumor activity, survival, and function in hostile tumor microenvironments
	Advancements in Vector Technology 46–47, 49–52	Improve gene delivery efficiency and safety	Optimization of viral vectors (lentiviral, retroviral) for stable gene transfer and reduced oncogenesis risk, non-viral methods (transposon-based systems, mRNA electroporation, CRISPR) for scalable and precise gene editing	Enhanced transduction rates, long-term CAR gene expression, increased safety and therapeutic efficacy
	Targeting specific T cell subsets 54, 55	Maximize therapeutic persistence and efficacy	Selection of Tcm and Tscm for longevity and potent antitumor responses, inclusion of both CD4+ and CD8+ T cells for synergistic effects	Enhanced long-term antitumor activity, durability, and therapeutic outcomes
	Optimizing Production and Reducing Costs 154–172	Streamline production, enhance efficiency, and reduce costs	Automated manufacturing systems, point-of-care production units, advanced cell expansion techniques, AI and ML integration, non-viral gene transfer methods, economic analysis, local manufacturing facilities, streamlined regulatory approvals	Reduced production time and costs, increased efficiency, improved accessibility, standardized treatments, expanded access in underserved regions, enhanced regulatory compliance
Targeting Novel Antigens	Tumor-specific and neoantigens 65–67	Expand efficacy across diverse cancer types	Identifying and targeting tumor-specific antigens (TSAs) and neoantigens unique to cancer cells	Minimized off-target effects, personalized treatment, broader therapeutic applicability
	Targeting cancer stem cells (CSCs) 75–77	Eradicate sources of tumor regrowth and metastasis	Engineering CAR T cells to recognize and eliminate CSC-specific antigens	More durable responses, reduced likelihood of cancer relapse
Enhancing Solid Tumor Targeting	Enhancing homing and penetration 78–82	Improve CAR T-cell trafficking and infiltration in tumors	Engineering CAR T cells to express chemokine receptors, incorporate matrix-degrading enzymes, and target tumor vasculature	Enhanced trafficking and infiltration, direct tumor starvation, boosted antitumor efficacy
	Overcoming the immunosuppressive TME 39–41, 83–88	Counteract the suppressive effects of the tumor environment	Development of "armored" CAR T cells, PD-1–CD28 switch receptors, knockdown of intracellular inhibitors, metabolic adaptations, and inhibition of tumor-derived exosomes	Improved CAR T-cell survival and function in hostile TME, enhanced anti-tumor activity
Synergistic Combination Therapies	Integration with Other Cancer Treatments 95, 96, 98–103, 108, 109, 111–115	Overcome barriers in immunotherapy and enhance CAR T cell efficacy	Combination with ICIs, TKIs, DNA damage repair inhibitors, angiogenesis inhibitors, low-dose chemotherapy, radiation therapy, oncolytic viruses, and BiTEs	Synergistic anti-tumor effects, enhanced CAR T cell functionality, better local control in solid tumors, reduced antigen escape
Allogeneic CAR T-cell Therapy	Allogeneic CAR T-cell Therapy 116–119, 121–125	Provide a standardized, ready-to-use treatment option	Use healthy donor T cells, bulk manufacturing, genetic modifications to prevent GVHD (e.g., TCR knockout, ADR integration)	Immediate availability, reduced manufacturing time and costs, consistent therapeutic outcomes
Advanced Strategies to Mitigate Toxicities	Enhancing Safety and Control 127–143	Reduce toxicities and enhance control in CAR T-cell therapies	Integration of safety switches (inducible caspase-9, ADCC switches), small molecule-based switches, SUPRA CARs, Dual CARs, inducible promoters, drug-responsive elements, sound/light activation	Rapid elimination of CAR T cells in severe side effects, precise targeting, reduced off-target effects, minimized risk of overactivation and associated toxicities
	Local delivery of CAR T cells 89–144	Minimize systemic exposure and reduce widespread toxicities	Administering CAR T cells directly to the tumor site	Reduced risk of widespread toxicities, enhanced local control of tumors
	Prophylactic Medications and Predictive Techniques145–153	Reduce severity of CRS and neurotoxicity, predict and manage toxic responses	Use of medications like tocilizumab and anakinra, biomarker monitoring, fractionated dosing, CRISPR/Cas9 gene editing, development of mouse models	Preemptive reduction of CRS and neurotoxicity, better prediction and management of toxic responses, identification of key inflammatory pathways, improved safety interventions