A phase I clinical trial of autologous HER2 CMV bispecific CAR T cells for progressive Glioblastoma

Transcription

1 A phase I clinical trial of autologous HER2 CMV bispecific CAR T cells for progressive Glioblastoma Nabil Ahmed, Vita Brawley, Oumar Diouf, Amada Corder, Aidin Ashoori, Alexia Ghazi, Claudia Gerken, Joanna Yi, Hao Liu, Cliona Rooney, Gianpietro Dotti, Adrian Gee, Robert Grossman, Yvonne Kew, David Baskin, Jonathan Zhang, Pamela New, John Hicks, Suzanne Z Powell, Winfried Wels, Malcolm Brenner, Helen Heslop and Stephen Gottschalk

2 Disclosure Collaborative research agreement with Aurora Biopharma for developing HER2 CAR studies managed by Baylor College of Medicine

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4 Glioblastoma OS 12.4 months OS 14.6 months 5 years OS < 3.4% Surgery children years OS <15% GBM ~25% TMZ Stupp et al. NEJM 2005.

5 Targeting HER2 in GBM Patient 1 Patient 5 Patient 2 V L V H CD28 ζ HER2 CAR % Cr release :1 20:1 10:1 5: :1 20:1 10:1 5:1 T cell : Tumor :1 20:1 10:1 5:1 CD133 ( ) x HER2 CAR T cells CD133 ( ) x NT T cells Wels et al. Biotech 92; Ahmed and Salsman et al. Clin Can Res 2009

6 Targeting HER2 in GBM Patient 1 Patient 5 Patient 2 V L V H CD28 ζ SSC 60 CD133-PE HER2 CAR % Cr release :1 20:1 10:1 5: :1 20:1 10:1 5:1 T cell : Tumor :1 20:1 10:1 5:1 CD133 (+) x HER2 CAR T cells CD133 ( ) x HER2 CAR T cells CD133 (+) x NT T cells CD133 ( ) x NT T cells Wels et al. Biotech 92; Ahmed and Salsman et al. Clin Can Res 2009

7 Regression of Autologous GBM day 6 day 9 day 12 day 15 Autologous GBM HER2.CD28.ζ T cells NT T cells Tumor only Ahmed and Salsman et al. Clin Can Res 2009

8 CMV and GBM An Evolving Relationship CMV pp65 CMV IE CMV pp65 + CMV IE /22 (50%) 19/22 (86%) Scheurer. Act Neuropath 08; Cobbs. Can Res 03; Mitchelle. Neoronc 08 Ghazi. J ImmRx 2012; Pediatric data by Corder et al (in review)

9 Rationale HER2 CAR GBM T cell Rossig et al. Blood 2002; Savoldo et al. Blood 2007; Pule et al. Nat Med 2008

10 HERT-GBM HER2 CAR CMV T cells in GBM patients HER2 CAR GBM CTL CMV CD4+ CMV CTL Offset Tumor Escape Activation Signal Native αβtcr Survival Signal HERT-GBM: NCT

11 HERT-GBM: objectives Primary Safety Secondary Persistence of infused T cells Anti-tumor activity of T cells HERT-GBM: NCT

12 HERT-GBM: eligibility Subject Tumor T cells Progressive GBM CMV seropositive KPS/LPS 50 HER2 + 15% HER2 CAR 20% killing No therapy 4 wk before 6wk after Organ functions Birth Control Consent Excluded HIV Infection Pregnancy Lactation Murine Allergy HERT-GBM: NCT

13 Subjects UPN Age Sex Surgery XRT +TMZ Salvage Therapies Investigational 1 45 F 3 +x M M 1 +x M NO M F F M 1 + NO M F M M F M F 2 + NO F 4 + NO F /14

14 HERT-GBM: product generation Lab EBV Retrovirus B BLOOD Ad.CMV pp65 LCL HER2.CAR T cell CTL CMV HER2 CTL CMV Rooney et al. The Lancet 1995; Pule et al. Nat Med 2009; Ghazi et al. J ImmunoRx 12

15 HERT-GBM: bispecificity CMV.pp65 CMV 7-63% CD8 PerCP HER2+ CMVpp65 +ve MDA-MB-468 autolo OKT3 blasts % 51 Cr release CMV + HER2 ~ % % HER2.CAR -FITC Subject 1 CMV.pp65 Elispot Reactivity median (range 390 to 1292 SFC/10 5 ) HER2-CAR median 67% (range: 46-82) Subject 2 40:1 20:1 10:1 5:1 40:1 20:1 10:1 5:1 T cell : target ratio Ghazi et al. J Immunotherapy 2011

16 Escalation Design Phase I dose escalation modified Continual Reassessment Method (mcrm) 1 x x x x 10 6 = 1 week = 6 weeks 1 x 10 6

17 CAR T cell Persistence UPN 13 Detected Not Detected Copies/ug DNA peripheral blood INFUSION INFUSION INFUSION number of samples Months post infusion 6 MON 1YR

18 CMV Immune Reconstitution 2.0 pp65/ie1 ratio Data past 6 weeks pending 0.0 Pre 1wk 2wk 4wk 6wk

19 Outcomes Patient number days post infusion * 1 yr 2 yr 3 yr * PD SD/PR followed by PD SD Survival following PD * Alive

20 17 year old male Thalamic tumor Unresectable Dose Level mm DL2 24mm MRI 10 months 71 year old female Parieto-temporal GTR Progressed Dose Level 4 DL4 x2 >24 months 15 year old female Fronto-caudate Debulk Progressed Dose Level 5 DL5 x2 >5 months

21 Survival from Diagnosis Overall survival probability Age at diagnosis <18 >=18 OS 24.8 months (from diagnosis) P= Months from diagnosis

22 Survival from 1 st Infusion Overall survival probability Age at diagnosis <18 >=18 OS 11.6 months (from infusion) P= Months from the 1 st infusion

23 HERT-GBM: summary Intent-to-treat: 20 lines; 17 subjects 5DL - Severe Adverse Events. none - Cytokine Release Syndrome. none Efficacy 1/16 unevaluable 8/16 (50%) PD 8/16 (50%) SD (7/16) or PR (1/16) 3/16 (19%) LTS >30 months HERT-GBM: NCT

24 Future Optimizing T cell Expansion v2.0 HDC Conditioning CTX 30 mg/kg/day on day -7, -6 Flu 25 mg/m2/day day -5 to -1 Rapidly generated HER2 CAR CMV CTLs pp65 and IE1 peptide pulsing (Ann Leen) Intracranial Delivery (icar-gbm) primary HER2 CAR T cells NCT Multiple reports from NCI and Gerdeman et al. Mol Ther 2012

25 THE PATIENTS Stephen Gottschalk Acknowledgments Center for Cell and Gene Therapy Baylor College of Medicine Baylor College of Medicine Texas Children s Hospital Houston Methodist Hospital The Methodist Research Institute (Y. Kew, R. Grossman, SZ Powell, D Baskin, J Zhang) Georg Speyer Haus (J Koch; W Wels)

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