Cancer Immunotherapy: CAR-T Cells, Checkpoint Inhibitors & Beyond

1. Immune Checkpoint Inhibitors

Checkpoint inhibitors block inhibitory receptors that tumors exploit for immune evasion. Anti-PD-1 antibodies (pembrolizumab, nivolumab) block PD-1/PD-L1 interaction, reactivating exhausted T cells. Response rates: 20–40% in melanoma, NSCLC, renal cell carcinoma. Anti-CTLA-4 (ipilimumab) enhances T cell priming — first checkpoint inhibitor approved (2011, melanoma). Combination anti-PD-1 + anti-CTLA-4 achieves 58% response in melanoma but increases immune-related adverse events (irAEs) to 55%. Novel targets: LAG-3 (relatlimab), TIM-3, TIGIT, VISTA.

2. CAR-T Cell Therapy

Chimeric Antigen Receptor T cells are engineered to express synthetic receptors targeting tumor antigens. Process: leukapheresis → T cell isolation → viral transduction with CAR construct → expansion → lymphodepletion → infusion. FDA-approved products: tisagenlecleucel (Kymriah, CD19, B-ALL), axicabtagene ciloleucel (Yescarta, CD19, DLBCL), brexucabtagene (Tecartus, MCL), idecabtagene vicleucel (Abecma, BCMA, myeloma). CR rates: 83% in pediatric B-ALL. Challenges: cytokine release syndrome (CRS, 30–94%), neurotoxicity (ICANS), antigen escape, solid tumor barriers.

3. Cancer Vaccines

Therapeutic vaccines train immune system against established tumors. Personalized neoantigen vaccines: sequence tumor exome → predict MHC-binding neoantigens → manufacture mRNA/peptide vaccine. mRNA-4157 (Moderna) + pembrolizumab reduced recurrence 44% vs. pembrolizumab alone in melanoma (KEYNOTE-942). Sipuleucel-T (Provenge): first FDA-approved cancer vaccine (2010, prostate cancer). Oncolytic viruses (talimogene laherparepvec/T-VEC): engineered HSV-1 replicates in tumors, releases GM-CSF. Next-generation: self-amplifying RNA, adjuvant optimization, combination with checkpoint blockade.

4. Bispecific Antibodies & Novel Formats

Bispecific antibodies simultaneously bind tumor antigen and T cell (CD3). Blinatumomab (BiTE): CD19×CD3 for B-ALL, 43% CR. Teclistamab: BCMA×CD3 for multiple myeloma, 63% ORR. Glofitamab: CD20×CD3 with 2:1 format for DLBCL. Advantages over CAR-T: off-the-shelf, no manufacturing delay. Antibody-drug conjugates (ADCs): trastuzumab deruxtecan (HER2, breast cancer), enfortumab vedotin (Nectin-4, bladder). T cell engagers, NK cell engagers, and trispecific antibodies in development.

5. Combination Strategies

Optimal immunotherapy requires rational combinations. Chemo-immunotherapy: chemotherapy induces immunogenic cell death, releases neoantigens. KEYNOTE-189: pembrolizumab + chemo → 22-month OS in NSCLC. IO-IO combos: anti-PD-1 + anti-CTLA-4 (CheckMate 214, renal), anti-PD-1 + anti-LAG-3 (RELATIVITY-047, melanoma). Targeted therapy + IO: lenvatinib + pembrolizumab in endometrial cancer. Radiation + IO: abscopal effect — local radiation triggers systemic immune response. Biomarkers: PD-L1 TPS, TMB, MSI-H, TIL density guide treatment selection.

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