1、The Battle Between CAR T and TumorsOutlineBackgroundPractice Steps CAR T for malignanciesSafetyExpectationBackgroundBasic knowledge about tumorsBasic Structure HistoryFridman W H, Pags F, Sauts-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcomeJ. Nature Reviews Canc

2、er, 2012, 12(4): 298-306.something you need to know about tumorsMicroenvironment of tumor:Structure of CAR t cellExtracellular target-binding domainHinge domainTrans-membrane domainIntracellular signaling domain/search?hl=zh-CN&q=car+t+cells+leukemia&tbm=isch&imgil=4ICYK7sAPPD-WM%253A%253BDSquHoDKqX

3、-LgM%253Bhttp%25253A%25252F%25252F%25252Fspa718%25252F10-elizabeth-j-shpall&source=iu&pf=m&tbs=simg:CAES0QEazgELEKjU2AQaAggADAsQsIynCBpiCmAIAxIouQy6DJsX5RbJA48ZlBfsF4kMxAOcPeEz4zOdPe4_1kzeMNJ49wT6VNxowOXko3uAHcw5BHaYoEVtSfgrQYjOigjke_1KG1mLLjtrXnR0nnE53GZki5i_1_1XzY5ZIAMMCxCOrv4IGgoKCAgBEgRMR51XDAsQ

4、ne3BCRo8CgYKBHRleHQKCQoHcHJvZHVjdAoKCghvcmdhbmlzbQoQCg5wcm9kdWN0IGRlc2lnbgoJCgdwcm9kdWN0DA&fir=4ICYK7sAPPD-WM%253A%252CDSquHoDKqX-LgM%252C_&biw=1366&bih=636&usg=_-g8pBwyas7XaFxNxjtjMBRD3oms%3D&ved=0ahUKEwig0bKm1_TJAhUQ72MKHX9tDPkQyjcIQg&ei=wv17VqDoDJDejwP_2rHIDw#imgrc=4ICYK7sAPPD-WM%3A&usg=_-g8pBwya

5、s7XaFxNxjtjMBRD3oms%3DUrba WJ, Longo DL. N Engl J Med 2011;365:754-757.What is the most optimal structure?Position of epitopeDistance to cell surfaceCAR lengthProtrusion from the membraneMichel Sadelain et al. Cancer Discovery 2013;3:388-398Dating Back late 1800s1989: first true CAR T cell was produ

6、cedTo date: over 100 anti-cd19 cases “construction of chimeric T cell receptors with anti-tumor specificity will enable testing of the feasibility of this approach in combating human tumors.”Gideon Gross,1989Practice stepsCollectionModificationExpansion HomingPersistenceMato A, Porter D L. A drive t

7、hrough cellular therapy for CLL in 2015: allogeneic cell transplantation and CARsJ. Blood, 2015, 126(4): 478-485.Practice stepsCollectionModificationExpansion HomingPersistenceGill S, Maus M V, Porter D L. Chimeric antigen receptor T cell therapy: 25years in the makingJ. Blood reviews, 2015.EXPANSIO

8、N ProblemIn vitro or in vivo,Which is more important?Select central memory CD8+ cell first!EXPANSION ProblemRiddell S R, Sommermeyer D, Berger C, et al. Adoptive Therapy with Chimeric Antigen Receptor Modified T Cells of Defined Subset CompositionJ. Cancer journal (Sudbury, Mass.), 2014, 20(2): 141.

9、How to persist long enough?Fridman W H, Pags F, Sauts-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcomeJ. Nature Reviews Cancer, 2012, 12(4): 298-306./about-emily-whitehead/CAR T for tumorsB cell malignanciesCD19 is most popularGill S, Maus M V, Porter D L. Chimeri

10、c antigen receptor T cell therapy: 25years in the makingJ. Blood reviews, 2015.Lymphodepletion2nd generation is betterALL is most treatableCytokine release syndromeNo dosage effect between number of CAR T and Response6. No relation between tumor burden and response Why do we choose CD19?Blml et al.

11、Arthritis Research & Therapy 2013 15(Suppl 1):S4 doi:10.1186/ar3906B-CLLB-ALL LIMITATION！CAR T for tumors acute myeloid leukemia (AML)Suicide geneExtracellular domain susceptible to depletionHodgkin lymphomaCD30T cell malignanciesFratricideAnti-CD5 CARMyelomaIncurableSolid tumorSafetyB cell aplasiaT

12、umor lysis syndromeNeural toxinMutation caused by virusCytokine release syndromeon-target, off tumor responsesCytokine release syndromeHigh fever, hypotension, potentially organ failureReduced dosage does not workReduce tumor burdenAssociated with IFN and TNF Kochenderfer J N, Dudley M E, Feldman S

13、A, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptortransduced T cellsJ. Blood, 2012, 119(12): 2709-2720.on-target, off tumor responsesProblem targetHer2PSMAROR1SolutionBlock normal antigenMulti-tar

14、getLocal drug deliverySome ExpectationThanks!ME E. The dizzying journey to a new cancer arsenalJ. 2013.ReferenceFridman W H, Pags F, Sauts-Fridman C, et al. The immune contexture in human tumours: impact on clinical outcomeJ. Nature Reviews Cancer, 2012, 12(4): 298-306.Urba W J, Longo D L. Redirecti

15、ng T cellsJ. N Engl J Med, 2011, 365(8): 754-7.Sadelain M, Brentjens R, Rivire I. The basic principles of chimeric antigen receptor designJ. Cancer discovery, 2013, 3(4): 388-398.Gill S, Maus M V, Porter D L. Chimeric antigen receptor T cell therapy: 25years in the makingJ. Blood reviews, 2015.Gross

16、 G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificityJ. Proceedings of the National Academy of Sciences, 1989, 86(24): 10024-10028.Mato A, Porter D L. A drive through cellular therapy for CLL in 2015: allogeneic c

17、ell transplantation and CARsJ. Blood, 2015, 126(4): 478-485.Riddell S R, Sommermeyer D, Berger C, et al. Adoptive Therapy with Chimeric Antigen Receptor Modified T Cells of Defined Subset CompositionJ. Cancer journal (Sudbury, Mass.), 2014, 20(2): 141.Bluml S, McKeever K, Ettinger R, et al. B-cell t

18、argeted therapeutics in clinical developmentJ. Arthritis Res Ther, 2013, 15(Suppl 1): S4.Kochenderfer J N, Dudley M E, Feldman S A, et al. B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptortransduced T cellsJ. Blood,