Immunotherapy for Malignant Brain Cancer: Overcoming Immune Suppression to Improve the Clinical Experience

Transcription

1 Immunotherapy for Malignant Brain Cancer: Overcoming Immune Suppression to Improve the Clinical Experience Derek Wainwright, PhD Assistant Professor Departments of Neurological Surgery, Microbiology-Immunology & Medicine-Division of Hematology/Oncology

2 Overall survival in advanced melanoma patients treated with PD-1 and/or CTLA-4 antibodies Wolchok et al., 217; New England Journal of Medicine

3 Overall Survival Overall survival in recurrent glioblastoma patients treated with PD-1 or VEGF-A antibodies (n=184) (n=185) Months Reardon et al., 217; Neuro-Oncology

4 Overall Survival Overall survival in recurrent glioblastoma patients treated with PD-1 or VEGF-A antibodies Is there an immunological difference between glioblastoma (n=184) (n=185) and melanoma? Months Reardon et al., 217; Neuro-Oncology

5 Melanoma and glioblastoma patients have different associations between survival and T cell infiltration Glioblastoma Pts. Low T cell infiltration (n=97) High T cell infiltration (n=26) Melanoma Pts. Low T cell infiltration (n=219) High T cell infiltration (n=149) Zhai.Wainwright, 218; Cell and Molecular Immunology

6 Immune exclusion - Predominantly absent for T cells (cold) - Vascular barrier - Absence of DC - Absence of T cell-recruiting chemokines - High degree of methylation (ie. midh) Tumor-Induced vs. Immunosuppression - Infiltrated by T cells (hot) - Increased levels of: - TGFb - PD-L1 - IDO1 - IL-1 - pstat3 - Treg - MDSC - Loss of antigen - Loss of MHC - Tolerogenic DC

7 Immune exclusion - Predominantly absent for T cells - Vascular barrier - Absence of DC - Absence of Th1 chemokines - High degree of methylation (ie. midh) Leads to: Immunosuppression - Infiltrated by T cells - Increased levels of: - TGFb - PD-L1 - IL-1 - IFNa/b/g - Treg - MDSC - Loss of antigen - Tolerogenic DC Ladomersky et al., 215; Oncommunology

8 Immune exclusion - Predominantly absent for T cells - Vascular barrier - Absence of DC - Absence of Th1 chemokines - High degree of methylation (ie. midh) Leads to: Immunosuppression - Infiltrated by T cells - Increased levels of: - TGFb - PD-L1 - IL-1 - IFNa/b/g - Treg - MDSC - Loss of antigen - Tolerogenic DC Ladomersky et al., 215; Oncommunology

9 Weller et al., 217; Lancet Oncology

10 Antigen escape is one immunosuppressive mechanism that may have contributed to Rintega failure CD8 GBM Cell Cytolytic T cell CD3 MHC I CD8 + EGFRvIII + IFN-g Survival Perforin Granzyme EGFRvIII - Outgrowth Sampson et al., 21; Journal of Clinical Oncology

11 Treg accumulation is another immunosuppressive mechanism why Rindopepimut therapy may have failed CD25 Treg FoxP3 CD25 Treg FoxP3 CD8 GBM Cell CD3 MHC I CD8 + EGFRvIII + Survival Cytolytic T cell Perforin Granzyme Outgrowth CD25 IFN-g Treg FoxP3 Sampson et al., 212; PLoS One Mitchell et al., 212; Blood

12 CAR T cells targeting EGFRvIII enhance immunosuppression in patient glioblastoma post-infusion O Rourke et al., 217; Science Translational Medicine

13 CAR T cells targeting EGFRvIII enhance immunosuppression in patient glioblastoma post-infusion O Rourke et al., 217; Science Translational Medicine

14 Wainwright et al., 212; Clinical Cancer Research Tumor cell IDO1 decreases overall survival in an immunocompetent GBM model ***

15 % Overall Survival (Glioblastoma Patients) High IDO1 expression is associated with decreased glioblastoma patient survival IDO1 low (n=121) IDO1 high (n=44) Months Zhai Wainwright et al., 217; Clinical Cancer Research *

16 Infiltrating T cells specifically increase IDO1 expression in human glioblastoma Zhai Wainwright, 217; Clinical Cancer Research

17 Infiltrating T cells specifically increase IDO1 expression in human glioblastoma Can we inhibit IDO1 and achieve a survival benefit? Zhai Wainwright, 217; Clinical Cancer Research

18 Percent Survival A GL261 Monotherapy with an IDO1 enzyme inhibitor does not increase survival against mouse glioblastoma C 1 Wild-type mice ic. unmodified GL261 C o n tro l (n = 7 ) ID O 1 in h ib ito r (B G B ; n = 8 ) IDO1 inhibitor B Days post-gbm intracranial (dp-ic.) 14dp-ic Days Post-Intracranial Injection Ladomersky Wainwright, 217; Clinical Cancer Research

19 Percent Survival A GL261 Monotherapy with an IDO1 enzyme inhibitor does not increase survival against mouse glioblastoma Can we combine C Wild-type mice ic. unmodified GL261 IDO1 inhibition C o n tro l (n = 7 ) ID O with 1 in h ib ito r (B G B ; n = 8 ) 1 B IDO1 inhibitor a standard of care Days post-gbm intracranial (dp-ic.) 14dp-ic. treatment to achieve 5 14 a survival 2 5 benefit? Days Post-Intracranial Injection Ladomersky Wainwright, 217; Clinical Cancer Research

20 Percent Survival A Dual radiotherapy (RT) with IDO1 enzyme inhibitor fails to increase long-term survival in a glioma model GL261 2Gy Rad. IDO1 inhibitor C 1 Wild-type mice ic. mouse GBM cells Ig G C o n tr o l (n = 7 ) ID O 1 in h ib ito r (B G B ; n = 8 ) R T (n = 8 ) ID O 1 in h ib ito r + R T (n = 8 ) B Days post-gbm intracranial (dp-ic.) 14dp-ic Days Post-Intracranial Injection Ladomersky.Wainwright, 218; Clinical Cancer Research *

21 Reading to my daughter got me thinking Zoey Wainwright

22 Reading to my daughter got me thinking Zoey Wainwright IDO1 inhibitor

23 Reading to my daughter got me thinking Radiation Zoey Wainwright IDO1 inhibitor

24 Reading to my daughter got me thinking? Radiation Zoey Wainwright IDO1 inhibitor

25 Overall Survival PD-1 blockade fails to increase recurrent glioblastoma patient survival as a monotherapy Months Reardon et al., 217; Neuro-Oncology

26 Overall Survival PD-1 blockade fails to increase recurrent glioblastoma patient survival as a monotherapy Will the triple combination of IDO1 inhibitor, radiation and PD-1 antibody synergize to achieve a long-term survival benefit? Months Reardon et al., 217; Neuro-Oncology

27 Percent Survival A B GL Simultaneous treatment with IDO1 inhibitor, radiotherapy and PD-1 blockade, durably increases survival against glioma dp-ic. 42 Days post-gbm intracranial (dp-ic.) PD-1 mab 2Gy Rad. IDO1 inhibitor C Ig G C o n tr o l (n = 7 ) R T (n = 8 ) P D 1 m A b + R T (n = 1 ) ID O 1 in h ib ito r + R T (n = 8 ) Wild-type mice ic. mouse GBM cells ID O 1 in h ib ito r (n = 8 ) P D 1 m A b (n = 8 ) ID O 1 in h ib ito r + P D 1 m A b (n = 9 ) ID O 1 in h ib ito r + R T + P D 1 m A b (n = 9 ) *** Days Post-Intracranial Injection Ladomersky.Wainwright, 218; Clinical Cancer Research

28 Percent Survival A GL261 B 14 Simultaneous treatment with IDO1 inhibitor, radiotherapy and PD-1 blockade, durably increases survival against glioma dp-ic. 42 Days post-gbm intracranial (dp-ic.) PD-1 mab 2Gy Rad. C BGB-5777 IDO1 inhibitor Ig G C o n tr o l (n = 7 ) R T (n = 8 ) P D 1 m A b + R T (n = 1 ) ID O 1 in h ib ito r + R T (n = 8 ) Wild-type Wild-type mice mice ic. ic. unmodified mouse GBM GL261 cells ID O 1 in h ib ito r (n = 8 ) P D 1 m A b (n = 8 ) ID O 1 in h ib ito r + P D 1 m A b (n = 9 ) ID O 1 in h ib ito r + R T + P D 1 m A b (n = 9 ) *** *** Days Post-Intracranial Injection Ladomersky.Wainwright, 218; Clinical Cancer Research

29 Principal Investigator: Rimas Lukas, MD (Northwestern U.) 1 Objective: Explore the feasibility and toxicity of simultaneous standard radiotherapy, PD-1 mab and IDO1 inhibitor treatment in newly-diagnosed adult patients with glioblastoma. Clinical Protocol Approved by BMS Currently Undergoing SRC/IRB Approval

30 Already, we are asking questions to improve Principal Investigator: Rimas Lukas, MD (Northwestern U.) future clinical efficacy 1 Objective: Explore the feasibility and toxicity of simultaneous standard radiotherapy, PD-1 mab and IDO1 inhibitor treatment in newly-diagnosed adult patients with glioblastoma. Clinical Protocol Approved by BMS Currently Undergoing SRC/IRB Approval

31 Percent Survival TMZ does not improve the OS benefit of trimodal immunotherapy in a GBM model A B GL dp-ic. 42 Days post-gbm intracranial (dp-ic.) TMZ PD-1 mab 2Gy Rad. IDO1 inhibitor C Wild-type mice ic. mouse GBM cells ID O 1 i + R T + P D 1 m A b (n = 1 ) ID O 1 i + R T + P D 1 m A b + T M Z (n = 1 ) 2 5 P= Days Post-Intracranial Injection Ladomersky.Wainwright, 218; Clinical Cancer Research

32 Percent Survival Trimodal immunotherapy is less effective for treating glioma in old age Y o u n g ; C o n tro l (n = 1 ) O ld ; C o n tro l (n = 1 2 ) 1 Y o u n g ; R T + P D -1 m A b + ID O 1 i (n = 1 ) O ld ; R T + P D -1 m A b + ID O 1 i (n = 8 ) **** Days Post-Intracranial (ic.) Injection Ladomersky.Wainwright, 218; Clinical Cancer Research

33 Summary/Future Considerations Exhaustively search for weaknesses in the trimodal immunotherapeutic approach, to improve the efficacy of future derivative clinical trials for GBM patients.

34 ACKNOWLEDGEMENTS Rimas Lukas, MD Erik Ladomersky, PhD Kristen Lauing, PhD Lijie Zhai, PhD Alecia Lenzen, MD Roger Stupp, MD C. David James, PhD James Chandler, MD Matt Lesniak, MD Craig Horbinski, MD/PhD