Slide 1: Novel approaches for rendering CAR T cells finally effective against gynecologic malignancies
Novel approaches for rendering CAR T cells finally effective against gynecologic malignancies DISCLOSURES Consultant for: Compass Therapeutics (till 2020), Anixa Biosciences, Alloy Therapeutics, Hibiscus Bioventures. Grant/Research support from: Compass Therapeutics (till 2020), Anixa Biosciences. S
Slide 2: Engineered T cell adoptive transfer
Engineered T cell adoptive transfer Collect blood and Activate T cells isolate T cells through and transduce leukepheresis Remove tumor PI with syrinatic and isolate TiLs receptors, i3_ * | a | Patient CART cell ' Activate @ P rf and ee a f expand Infuse CAP} TILs | Tells Ory oye Infuse Infuse TCR]
Slide 3: Second generation CAR T cells: Basic elements
Second generation CAR T cells: Basic elements Va Va Recognition Domain<— Fv against ” : scrv against a ——— > Hinge/spacer surface Ag; PEP eperere From CD8 NKG2D obabd —> CD28, 4-1BB, OX40 Signaling Domains 4-1BB ad appears to enhance ersistence -Lentiviral/retroviral transduction or RNA electroporat
Slide 4: Most current CAR T cell targets in solid tumors are shared with vital healthy tissues
Most current CAR T cell targets in solid tumors are shared with vital healthy tissues Target Disease B7-H3? CAIX CD70 CEA Claudin 18.2 EGFR EpCam FSHR GD2 GPC3 HER-2 IL13Ralpha2 ICAM-1 KLK2 Mesothelin MUC1? NKG2D ligands PSCA PSMA ROR1 TAG72 Hepatocellular Carcinoma, Non-Small Cell Lung Cancer, Panc
Slide 5: FSHCER T cells targeting FSHR+ ovarian cancer
FSHCER T cells targeting FSHR* ovarian cancer (NCT05316129; clinical trial, recruiting) FSHB CD8a hinge and signal transmembrane peptide domain FSHB CGa 4-1BB CD3z PI: R Wenham, MD Moffitt Cancer Center Perales-Puchalt et al; Clin Cancer Res. 2017. Co-stimulatory 1BB..... NCT05316129: Autologous CD3
Slide 6: FSHR is NOT expressed in non-ovarian healthy human tissues
FSHR is NOT expressed in non-ovarian healthy human tissues wW N j=) oO o 0.002 0.0015- 0.001 - te) =] (=) o 0 uolssaudxs YNYW YHS-4 eanejey Perales-Puchalt et al; Clin Cancer Res. 2017.
Slide 7: FSH-re-directed primary human T cells effectively target patient-derived FSHR+ tumors in vivo
FSH-re-directed primary human T cells effectively target patient- derived FSHR+ tumors in vivo Tumor volume (mm?) 0. 0 FCCC226 -—m FSHCER -a- Mock 10 20 30 40 50 60 70 Time(days) 112006 500 Ee = FSHCER £400) 4 Mock 2 300. 3 S 200: 2 100 5 F of —_—_——_——_— 0 150 155 160 165 Time (days) Pe CS C pre Ro
Slide 8: FSH-re-directed autologous human T cells effectively target orthotopic patient-derived FSHR+ tumors in vivo (II)
FSH-re-directed autologous human T cells effectively target orthotopic patient-derived FSHR+ tumors in vivo (Il) Mock 14-107 FSHCER Perales-Puchalt et al; Clin Cancer Res. 2017.
Slide 9: ID8-Defb29-Vegf-a i.p. injected tumor cells cause massive ascites and multiple peritoneal tumor masses
ID8-Defb29-Vegf-a i.p. injected tumor cells cause massive ascites and multiple peritoneal tumor masses in 35-40 days Day 40 after tumor injection
Slide 10: FSH-re-directed mouse T cells effectively target orthotopic FSHR+ tumors in immunocompetent hosts
FSH-re-directed mouse T cells effectively target orthotopic FSHR+ tumors in vivo in immunocompetent hosts ** ; |.P. Ovarian tumor N=15 mice/group a independent as — FsHICER 10e6 CERT cells experiments Days 7/14 0 60 65 Time (days) Survival (%) te
Slide 11: NCT05316129: Dose-escalation first-in-human clinical trial in recurrent/chemoresistant ovarian Ca
NCT05316129: Dose-escalation first-in-human clinical trial in recurrent/chemoresistant ovarian Ca -PI: R Wenham, MD (NCT05316129; all Moffitt ovarian cancer patients; Moffitt CT Facility) -I.P. vs. |.V.> Comparative safety and effectiveness -CAR T cell persistence/suppression, features of the infusi
Slide 12: TAKE HOME MESSAGE
TAKE HOME MESSAGE >Tumor targeting can be achieved without killing vital tissues (==, OR2H1, others?). >Only by targeting antigens not expressed in vital tissues we will be able to develop effective interventions against solid tumors, (7009) Gene)> engineering of T cells. >Low antigen expression can