医学免疫学课件：TCR-T immunotherapy

1、TCR-T immunotherapy Background PART ONEPART TWOPART THREEChallengesOutlineAdvancesPARTONEBackground市场化运作Variable immunoglobulin domain (V)Constant domains（C） Connecting peptide (cp)Transmembrane helix (TM)Cytoplasmic tail (cyto)Structure of TCR市场化运作Variable immunoglobulin domain (V)Constant domains（

2、C） Connecting peptide (cp)Transmembrane helix (TM)Cytoplasmic tail (cyto)Structure of TCR1. Timothy . et al. Strategies to genetically engineer T cells for cancer immunotherapy, Cancer Immunol Immunother (2016) 65:631649 Procedure2. Sharpe M, Mount N. Genetically modified T cells in cancer therapy:

3、opportunities and challenges. Disease Models & Mechanisms. 2015;8(4):337-350. doi:10.1242/dmm.018036.PARTTWOAdvances 010203AntigensPairing AffinityAdvancesDifferentiation antigensMART-1，gp100，CEA， (TRP)1and2 01 Over-expressed antigens表皮生长因子HER202Cancer Testis Antigens(CTAs) MAGE-A1，MAGE-C2，和NY-ESO1

4、03Neo-antigensp53，B-Rafkinase，CDK404Tumor-associated antigens(TAAs)Cancer/testis antigens (CTAs)5. Arash Salmaninejad. et al. (2016) Cancer/Testis Antigens: Expression, Regulation, Tumor Invasion, and Use in Immunotherapy of Cancers, Immunological Investigations, 45:7, 619-640, DOI: 10.1080/08820139

5、.2016.1197241 Neo-antigensNeoantigenic peptide may representNeoantigens predicted to have greater binding to an HLA allele than the wild-type peptideNeoantigens consists of those peptides that contain a mutation in residue that points toward the TCR and hence could impact binding to TCR Neoantigens

6、includes peptides that have a mutation in a residue that impacts the interaction both with the TCR and with the MHC6. Preeti Sharma. et al. Recent advances in T-cell engineering for use in immunotherapy， 19 Sep 2016, 5(F1000 Faculty Rev):2344 (doi: 10.12688/f1000research.9073.1) Native / Transduced

7、/“Mispaired” heterodimers Native /transduce Native /transduce ProblemsPossible TCRsTCR pairing MispairingSafetyUnknown specificityPotential autoimmune consequences (graft-versus-host disease) Efficacy Dilution of the signal transduction apparatus (CD3)Low efficiency of recognizing MHC complexTCR pai

8、ringCodon optimizationAddition of disulfide bondsAddition of leucine zipperModification of glycosylated residuesUse of single-chain VVC with a C chainPartial murinization of the constant regions Adding signaling domains to the intracellular portions of the transduced TCRCo-transfer of TCR and CD3Kno

9、ck down the endogenous TCR expressionsiRNA/shRNAZFNs/TALEN/CRISPR7. Marcela V. Maus. et al. Adoptive Immunotherapy for Cancer or Viruses，Annu. Rev. Immunol. 2014. 32:1892258. Changli Tao. et al. Imaging of T-cell receptor fused to CD3 reveals enhanced expression and improved pairing in living cells,

10、 International Journal of Molecular Medicine (2014) :849-855TCR/-CD3 fusionCompetition of TCR -chains (i.e. C versus TCR) for binding to a scTCR: C is able to compete with any TCR depending on their intrinsic competitive strengths Competition of TCR -chains (i.e. TCR versus scTCR) for binding to TCR

11、: TCR dominates binding to TCR to assemble to a native TCR Mispairing of a 3-domain scTCR with human TCR occurs with lower frequencies in human t-cells The novel V-Li(V) disulfide bond improved the functional and structural avidity of a fragile scTCR pp65 Use of single-chain VVC with a C chain9. Dia

12、na Knies. et al. An optimized single chain TCR scaffold relying on the assembly with the native CD3-complex prevents residual mispairing with endogenous TCRs in human T-cells, Oncotarget (2016):Vol. 7, No. 16 Domain-swapped T cell receptors 10. Bethune MT, Gee MH, Bunse M, et al. Domain-swapped T ce

13、ll receptors improve the safety of TCR gene therapy. Rath S, ed. eLife. 2016;5:e19095. doi:10.7554/eLife.19095.Domain-swapped T cell receptors 10. Bethune MT, Gee MH, Bunse M, et al. Domain-swapped T cell receptors improve the safety of TCR gene therapy. Rath S, ed. eLife. 2016;5:e19095. doi:10.7554

14、/eLife.19095.Domain-swapped T cell receptors 10. Bethune MT, Gee MH, Bunse M, et al. Domain-swapped T cell receptors improve the safety of TCR gene therapy. Rath S, ed. eLife. 2016;5:e19095. doi:10.7554/eLife.19095.Relationship between TCR affinity and T cell activity for CD8 and CD4 T cells Optimiz

15、e the activity of CD8 T cells against self-pepMHC (class I) Redirect the activity of CD4 T helper cells against a class II MHC target11. Jennifer D. TCR affinity for p/MHC formed by tumor antigens that are self- proteins: impact on efficacy and toxicity, Curr Opin Immunol. 2015 April ; 33: 1622. doi

16、:10.1016/j.coi.2015.01.003. Kd=TCRpepMHC/TCR: pepMHCPARTTHREEChallengesDrawbacksMHC restricted and target only a single antigenSubject to the inhibitory signalsMispairing of exogenous & endogenous chainsOn-target/off-tumor toxicityCytokine stormReference Tana O. et al. Retrieval of functional TCRs f

17、rom single antigen-specific T cells: Toward individualized TCR-engineered therapies, OncoImmunology, 2015;4:7, e1005523, DOI: 10.1080/2162402X.2015.1005523Sharpe M, Mount N. Genetically modified T cells in cancer therapy: opportunities and challenges. Disease Models & Mechanisms. 2015;8(4):337-350.

18、doi:10.1242/dmm.018036.Timothy . et al. Strategies to genetically engineer T cells for cancer immunotherapy, Cancer Immunol Immunother (2016) 65:631649 Lucas S, Coulie PG. About human tumor antigens to be used in immunotherapy. Semin Immunol (2008)20(5):3017. doi:10.1016/j.smim.2008.02.001.Arash Sal

19、maninejad. et al. (2016) Cancer/Testis Antigens: Expression, Regulation, Tumor Invasion, and Use in Immunotherapy of Cancers, Immunological Investigations, 45:7, 619-640, DOI: 10.1080/08820139.2016.1197241 Preeti Sharma. et al. Recent advances in T-cell engineering for use in immunotherapy， 19 Sep 2

20、016, 5(F1000 Faculty Rev):2344 (doi: 10.12688/f1000research.9073.1)Reference Marcela V. Maus. et al. Adoptive Immunotherapy for Cancer or Viruses，Annu. Rev. Immunol. 2014. 32:189225Changli Tao. et al. Imaging of T-cell receptor fused to CD3 reveals enhanced expression and improved pairing in living cells, International Journal of Molecular Medicine (2014) :849-855Diana Knies. et al. An optimized single chain