The future of cancer treatment: immunomodulation, CARs and combination immunotherapy

Khalil, D. N., Smith, E. L., Brentjens, R. J. & Wolchok, J. D. The future of cancer treatment: immunomodulation, CARs and combination immunotherapy. Nat Rev Clin Oncol 13, 273–290 (2016).

1년 전 논문이지만, 매우 잘 정리된 리뷰.

1. predictive biomarker : C-reactive protein (CRP), absolute lymphocyte count, and soluble CD25

2. CTLA-4 mechanism in Treg : CTLA-4 constitutively expressed in Treg → RNAseq in Treg and activated T 

3. RECIST → irRC

4. PD-L1 and PD-L2 are expressed on the surface of APCs and malignant cells, particularly in response to local inflammatory cytokines, such as IFNgamma.

5. PD-L1 binds to CD80 as well as PD-1 : distinct mechanism or irAE between PD-1 ab and PD-L1 ab.

6. TIGIT

7. 4-1BB : late co-stimulatory signal

8. GITR is unregulated when conventional T cells are activated, and is constitutively expressed by Treg cells.

9. Fludarabine conditioning: CAR-T persistance

10. CAR target antigen: AML (CD33, CD123), B (CD22 ,ROR1, CD30, Ig kappa light chain), MM (BCMA, CS1, CD38, CD138)

11. Challenges in solid by CAR: Immunosuppressive microenv, antigen heterogeneity, on-target toxicity

12. EGFRvIII for GBM and mucin-16 for ovarian cancer

13. CAR relapse by Antigen escape mechanism

14. Armoured CAR-T cells: PD-1/CD28 chimera, T cells co-expressing CD40L or 4-1BB, lead to the secretion of pro-inflammatory cytokines such as IL-2, IL-15, IL-12. 

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