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Advances in CAR-T Cell Therapy - Creative Biolabs
- 2. https://www.creative-biolabs.com/car-t 01 CAR Structure– Function Relationships 02 Ex Vivo and In Vivo Platforms for CAR-T Therapy 03 Key Milestones in CAR T Cell Development 04 Challenges in CAR-T Cell Therapy 05 Next-Generation CAR Enhancements 06 Next-Generation CAR-T Cell Therapy Platforms 07 CAR-T Platforms in Clinical Status 08 CAR-T Therapy Beyond Cancer 09 Targets of CAR-T Cell Therapies with Clinical Evidence of Efficacy Contents
- 3. https://www.creative-biolabs.com/car-t Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648. Baker, Daniel J., et al. "CAR T therapy beyond cancer: the evolution of a living drug." Nature 619.7971 (2023): 707-715.
- 4. https://www.creative-biolabs.com/car-t Baker, Daniel J., et al. "CAR T therapy beyond cancer: the evolution of a living drug." Nature 619.7971 (2023): 707-715.
- 5. https://www.creative-biolabs.com/car-t Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648.
- 6. https://www.creative-biolabs.com/car-t Sterner, Robert C., and Rosalie M. Sterner. "CAR-T cell therapy: current limitations and potential strategies." Blood cancer journal 11.4 (2021): 69. Immunosuppressive microenvironment CAR-T cell-associated toxicities On target/off tumor effects CAR-T cell trafficking and tumor infiltration Tumor antigen escape from CAR-T cell
- 7. https://www.creative-biolabs.com/car-t Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648. • Multispecificity and/or logic gating AND gates (split CAR, LINK CAR), OR gates (bivalent/bicistronic/two vectors), NOT gates (PD-1, CTLA-4, TIGIT), IF-THEN gates (synNotch) • Fitness enhancements Gene overexpression (c-Jun, BATF, PGC1A), gene knockout (PD1, TGFBR2, HPK1), small molecule (dasatinib, AKT inhibitor), suicide gene (EGFRt, HER2t, HSV-tk) • Regulatable platforms AP1903-inducible costimulation, antibody-coupled, fluorescein-CAR, switchable CAR T cells, SNIP, SUPRA, co- LOCKR • Armouring Dominant negative (TGFβR, PD-1, FAS), checkpoint (PD-1-Fc, anti-PD-1 scFv), cytokines (IL-12, IL-18), switch receptors (PD-1– CD28, IL-4R–IL-2Rβ), FAP-CAR, heparinase/catalase overexpression, solHVEM, PKA disruptor • Engaging the endogenous immune system Chemokine (CXCR5, CCR4, CCL19 ) overexpression, CD40L overexpression, RN7SL1 extracellular vesicles, FLT3L overexpression • Expansion and persistence IL-15/IL-7 secretion/sushi domain/ tethered/mutant constitutive, JAK–STAT CAR, ortho IL-2, IL-2–IL-9 chimera, chimeric costimulatory receptor • Alternative signalling TRuC, Ab-TCR, STAR • Stealth or fratricide resistant Knockout (TRAC, B2M, CIITA), overexpression (HLA-E, CD47), endoplasmic reticulum retention (CD7 PEBL, CD3 PEBL) • Alternative immune cells CAR-iNKT cell, CAR-γδ T cell, iPSC-derived CAR T cell, CAR-macrophage
- 8. https://www.creative-biolabs.com/car-t Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648.
- 9. https://www.creative-biolabs.com/car-t Verma, Malvika, et al. "The next-generation CAR-T therapy landscape." Nature reviews. Drug Discovery (2023).
- 10. https://www.creative-biolabs.com/car-t Advantages of CAR T therapy in other diseases in comparison to cancer. CAR T cells are poised to target a wide variety of diseases and pathological substrates. Baker, Daniel J., et al. "CAR T therapy beyond cancer: the evolution of a living drug." Nature 619.7971 (2023): 707-715.
- 11. https://www.creative-biolabs.com/car-t Target Disease Response rate Survival Comments Date of FDA approval CD19 LBCL CR: 58%, PFS: 44% at 12 months OS: 52% at 18 months Axi-cel approved as 3rd line treatment for LBCL (>18 yr of age) Oct 2017 CD19 LBCL CR: 40% RFS: 65% OS: 49% at 12 months Tis-cel approved as 3rd line treatment for LBCL (>18 yr of age) May 2018 CD19 MCL CR: 67% PFS: 61% OS: 83% at 12 months Brex-cel approved for R/R MCL (>18 yr of age) July 2020 CD19 FL CR: 74% PFS: 65% OS: 87% at 18 months Axi-cel approved as 3rd line treatment for R/R FL (>18 yr of age) Mar 2021 CD19 LBCL CR: 53% PFS: 44% OS: 58% at 12 months Liso-cel approved for 3rd line LBCL (>18 yr of age) Feb 2021 BCMA MM CR: 33% Median PFS: 8.8 months OS: 78% at 12 months Ide-cel approved for 5th line treatment for MM (>18 yr of age) Mar 2021 CD19 B-ALL CR: 56% RFS: 58% at 6 months OS: 71% at 12 months Brex-cel approved for R/R B-ALL (>18 yr of age) Oct 2021 BCMA MM sCR: 67% PFS: 77% OS: 89% at 12months Cilta-cel approved for 5th line MM (>18 yr of age) Feb 2022 CD19 FL CR: 69% PFS: 67% at 12 months Tis-cel approved for 3rd line treatment of FL (>18 yr of age) May 2022 CD19 LBCL (Axi-cel vs SOC) CR: 65% vs 32% (Axi-cel vs SOC) EFS: 41% vs 16% OS: 61% vs 52% at 24 months Axi-cel approved as 2nd line treatment for LBCL (>18 yr of age) April 2022 CD19 LBCL (Liso-cel vs SOC) CR: 66% vs 39% (Liso-cel vs SOC) EFS: 45% vs 24% OS: 79% vs 64% at 12 months Liso-cel approved as 2nd line treatment for LBCL (>18 yr of age) June 2022 Approved Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648.
- 12. https://www.creative-biolabs.com/car-t Target Disease Response rate Survival Comments CD19 LBCL CR: 78% PFS: 75% OS: 91% at 12 months Front line therapy for high-risk LBCL CD22 B-ALL CR: 70% Median RFS: 6 months Median OS: 13.4 months CD19-CAR T cell therapy had failed in 88% of these patients CD22 LBCL ORR: 86% Median PFS: not reached CD19-CAR T cell therapy had failed in 95% of these patients CD30 HL CR: 59% PFS: 36% OS: 94% at 12 months Greater CD30 CAR T persistence and higher PFS with fludarabine-based LD CD7 T-ALL CR: 90% Not available Allogeneic donor-derived CD7-CAR T cells; GVHD grade 1–2 in 60% of patients CD7 T-ALL or TLBL CR: 7/8 Not available Autologous CD7-CAR T cells rendered fratricide-resistant using a CD7 PEBL CD38 AML CR or CRi: 4/6 50% relapse rate at 6 months Allo-HSCT refractory patient population; no off-target effects on monocytes or lymphocytes κ light chain NHL, CLL, or CR: 2/9 Not available No or limited pre-treatment LD. One CR sustained for at least 3 yr CD20 LBCL CR: 54.5% PFS 41.7% at 24 months All patients had prior rituximab; longest CR at least 57 months Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648. Ongoing clinical trials - Hematological malignancies
- 13. https://www.creative-biolabs.com/car-t Target Disease Response rate Survival Comments GD2 NB CR: 27% of patients with active disease Median OS: 31 months 1st generation CAR expressed by EBV-reactive T cells; one patient had sustained CR for at least 60 months GD2 DMG 9/10 patients with radiographic or clinical benefit Not available Initial IV infusion followed by multiple ICV infusions; one patient had >95% reduction in tumor volume HER2 Sarcomas CR: 27% Not available No on-target, off-tumor toxicity of HER2-CARs; patient with RMS metastatic to bone marrow had a CR for >12 months IL-13Rα2 GBM CR: 1/1 Not available CR sustained for 7.5 months with 16 locoregional administrations over 220 days EGFR BTC CR: 6% Median PFS: 4 months One out of 17 patients achieved a CR for at least 22 months. Manageable mucosal toxicities. Mesothelin MPD 11% complete metabolic response by PET OS: 83% at 1 yr Median OS: 23.9 months Regionally delivered intrapleural CAR T cell administration plus PD-1 blockade Claudin-18.2 GC or PC ORR: 48.6% Disease control rate: 73.0% Median PFS: 3.7 months OS: 81% at 6 months 83% of patients showed tumor regression; 11% showed reversible grade 3/4 gastrointestinal toxicities PSMA MCRPC 5/13 patients had >30% reduction in PSA Median PFS: 4.4 months Median OS: 15.9 months PSMA CAR T cells expressing a dominant-negative TGFβRII. 5 out of 13 patients with high-grade CRS, one fatal CD19 SLE 1/1 clinical remission Not available Rapid decrease of autoantibodies from >5,000 U ml-1 to 4 U ml-1 Labanieh, Louai, and Crystal L. Mackall. "CAR immune cells: design principles, resistance and the next generation." Nature 614.7949 (2023): 635-648. Ongoing clinical trials - Solid tumors and non-malignant disease
- 14. https://www.creative-biolabs.com/car-t Confidential | Creative Biolabs CellRapeuticsTM
- 15. https://www.creative-biolabs.com/car-t CAR-T Solution Target Antigen Selection Highly Specific Antibody Screening CAR Design & Construction Virus Packaging T Cell Engineering CAR-T In Vitro Assays CAR-T Preclinical In Vivo Assays scFv Sequencing Data analysis Report delivery Confidential | Creative Biolabs CellRapeuticsTM 15
- 16. https://www.creative-biolabs.com/car-t As a trusted partner in the discovery and development of CAR-T cell immunotherapy, Creative Biolabs provides collaborative approaches and various solutions to help our clients bring a novel therapy to the clinical phase. We are committed to providing custom in vitro studies and solutions to reduce the potential risk and accelerate the studies. CAR Expression Test In Vitro Cytotoxicity Test Antigen Specific T Cell Activation Efficacy Test Cytokine ReleaseTest CAR Cell Proliferation Test Viability and Bio-distribution Analysis Single Cell Analysis for CAR- T T Cell-Mediated Tumor Cell Lysis Assay Multiplex Cytokine and Chemokine Assay Mixed Lymphocyte Tumor Reactivity Assay Enhancement or Inhibition of T Cell Response Assays Confidential | Creative Biolabs CellRapeuticsTM
- 17. https://www.creative-biolabs.com/car-t Creative Biolabs provides a comprehensive suite of in vivo studies, helping accelerate your path to discovery and translation to a clinical application. Construction of Animal Models In Vivo Efficacy Test of CAR-T Safety and Toxicity Evaluation of CAR-T Strategies to Harness Cytokine Release Syndrome Viability and Bio-distribution Study of CAR-T Quality Control of In Vivo Assays GMP-like Production Confidential | Creative Biolabs CellRapeuticsTM