Car T Cells in Solid Tumors: Overcoming Obstacles
Abstract
:1. Introduction
2. CART T Cells: Origins and Structure
3. Mechanisms of Action
4. Causes of Ineffectiveness in Solid Tumors
4.1. Antigens
4.2. Tumor Microenvironment
4.2.1. Immune Checkpoint Inhibitors
4.2.2. Physical Barriers
4.2.3. Metabolic Conditions
4.3. Trafficking into the Tumoral Area
5. Optimizations to Increase CAR T Cells’ Effectiveness in Solid Tumors
5.1. Specificity and Toxicity
5.2. Tumor Microenvironment
5.3. Trafficking and Infiltration into the Tumoral Area
6. Conclusions and Future Perspectives
Author Contributions
Funding
Conflicts of Interest
References
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Cancer Type | CAR T Model | Sample | Duration | Results | Reference |
---|---|---|---|---|---|
ALL | Kymriah | 97 patients | ≥3 months | ORR at 82%, CR at 62%, SR after 18 months at 70%, and CRS in 70% of cases, of which 48% were admitted to the ICU. | Fowler et al. [50] |
B-ALL | Tisagenlecleucel | 75 patients | 3 months | ORR at 81%, SR at 73% on average over 12 months, CRS in 77% of cases, and neurological events in 40% of patients. | Mueller et al. [51] |
ALL | CTL019 | 59 patients | 1 session | CR in 93% of patients, SR at 79%, RFS at 76%, and CRS prevalence at 88%. | Maude et al. [52] |
ALL | CTL019 | 30 patients | 1 month | RR at 87%; CRS in 28–30 of patients; neurotoxicity and B cell aplasia were observed | Maude et al. [53] |
LBCL | Axicabta gene Ciloleucel | 101 patients | 1 session | RR at 58%, neurological events in 32% of patients, and CRS grade III in 11% of cases. | Neelapu et al. [54] |
NHL | Lisocabtagene maraleucel | 344 patients | 2 sessions | CRS was observed in 73% of individuals, neurotoxicity was observed in 23%, NHL patients obtained 75% ORR and 55% CR, while DLBCL patients obtained an ORR at 80% and CR at 59%. | Abramson et al. [55] |
DLBCL | Tisagenlecleucel | 93 patients | 14 months | ORR at 53%, CR in 40% of cases and PR in the remaining 12%, RFS at 65%, CRS in 22% of patients, neurological adverse effects in 12% of cases, cytopenias in 32% of individuals, and prevalence of 20% in terms of infections. | Schuster et al. [41] |
DMG | T CAR Anti-GD2 | 5 patients | - | Drastic decrease in tumor size with a reduced number of residual GD2 glial cells and few adverse effects. | Mount et al. [56] |
Renal Carcinoma | T CAR Anti-CAIX | 12 patients | 10 sessions | Antigen-specific effects; reduced hepatotoxicity levels at low doses; no clinical effects recorded. | Lamers et al. [57] |
Ovarian Cancer | T CAR Anti-FR | 14 patients | 1 session | No tumor reduction was observed in patients, low levels of persistence and high tolerance. | Kershaw et al. [58] |
Prostate Cancer | Anti-PSMA dTc T CAR | 5 patients | 2 weeks | 2 out of 5 patients achieved RP regardless of dose size administered with IL-2 depletion; no toxicities or reactivity were recorded | Junghans et al. [59] |
Sarcoma | T CAR Anti-HER2 | 19 patients | 6 weeks | There was persistence for a period of approximately 6 weeks; without significant toxicities, 14 of the patients had stable disease and an OSR of 10.3 months | Kawakama et al. [60] |
Antigen | Tissue Expression | Cancer Type | Adverse Effects | Clinical Phase |
---|---|---|---|---|
CD19 | Physiological and transformed B cells | ALL, DLBCL, NHL, CLL, and other B cell malignancies. | CRS, CRES, B cell aplasia. | Phase I |
CD22 | B lymphocytes | B-ALL and B cell lymphoma | CRS and neurotoxicity | Phase I |
CD30 | Transformed B and T lymphocytes (expression is reduced in normal cells) | ACLC, HL, and T cell lymphomas | Significant adverse effects have not been observed | Phase I and phase II |
Her2/neu | Widely expressed in physiological cells | Oral, Gastric, lung, and breast cancer | High levels of cytotoxicity | Phase I |
EGFR | Skin, GI tract, Kidneys, and other normal tissues | HNSCC and lung, pancreatic, colorectal, and breast cancer | Nausea, vomit, dyspnea, or hypotension | Phase I |
HER2 | Widely expressed in normal tissues | Ovarian and breast cancer, osteosarcoma, GBM, and medulloblastoma | Lethal cytotoxicity and CRS | Phase I |
CAIX | Malignant kidney cells | Renal carcinoma | Severe cytotoxicity and hepatic infiltration | Phase I and phase II |
CEA | Colon, stomach, tongue, cervix, and prostate | Colorectal carcinoma, pancreatic adenocarcinoma, and breast cancer | Fever, Leukopenia, and grastritis | Phase I |
PSMA | Prostate | Prostate cancer | Well-tolerated; can course with neurotoxicity in some cases | Phase I |
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Rojas-Quintero, J.; Díaz, M.P.; Palmar, J.; Galan-Freyle, N.J.; Morillo, V.; Escalona, D.; González-Torres, H.J.; Torres, W.; Navarro-Quiroz, E.; Rivera-Porras, D.; et al. Car T Cells in Solid Tumors: Overcoming Obstacles. Int. J. Mol. Sci. 2024, 25, 4170. https://doi.org/10.3390/ijms25084170
Rojas-Quintero J, Díaz MP, Palmar J, Galan-Freyle NJ, Morillo V, Escalona D, González-Torres HJ, Torres W, Navarro-Quiroz E, Rivera-Porras D, et al. Car T Cells in Solid Tumors: Overcoming Obstacles. International Journal of Molecular Sciences. 2024; 25(8):4170. https://doi.org/10.3390/ijms25084170
Chicago/Turabian StyleRojas-Quintero, Joselyn, María P. Díaz, Jim Palmar, Nataly J. Galan-Freyle, Valery Morillo, Daniel Escalona, Henry J. González-Torres, Wheeler Torres, Elkin Navarro-Quiroz, Diego Rivera-Porras, and et al. 2024. "Car T Cells in Solid Tumors: Overcoming Obstacles" International Journal of Molecular Sciences 25, no. 8: 4170. https://doi.org/10.3390/ijms25084170