T-cell Exhaustion in Leukemia Relapse Post Allogeneic Stem Cell Transplantation

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1 T-cell Exhaustion in Leukemia Relapse Post Allogeneic Stem Cell Transplantation Hong Zheng, M.D., Ph.D. Assistant Professor of Medicine Penn State Hershey Cancer Institute Penn State University College of Medicine

2 Presenter Disclosure Information Hong Zheng M.D., Ph.D. The following relationships exist related to this presentation: No Relationships to Disclose 2

3 Allogeneic Stem Cell Transplant Shlomchik WD, Nature Reviews of Immunology, 2

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5 Graft versus Leukemia (GVL) and Graft versus Host Disease (GVHD)

6 Strategies to Enhance GVL Without Causing GVHD GVHD T?? Exhausted T? APC Allo Ag leukemia GVL

7 T cell Exhaustion Wherry EJ, Nature Immunol 211

8 Targeting PD-1/PD-L1 for cancer therapy

9 Targeting PD-1 in AML therapy? Blockade of PD-1 pathway improves relapse-free survival in animal AML models. Zhou Q et al., Blood 211 Gene expression of PD-L1 and PD-L2 are up-regulated in leukemia blast of MDS and AML patients. Yang H et al., Leukemia 213 miha-specific T cells express elevated PD-1 in a CML-AP and a AML patient post DLI. In vitro blockade of PD-1/PD-L1 pathway increased function of T cells from AML patients. Norde WJ et al., Cancer Research 211

10 Hypothesis T cell exhaustion may contribute to GVL failure and leukemia relapse post allosct. Targeting key mediators of T cell exhaustion can be a promising leukemia therapeutic.

11 Clinical characteristic of patients Patient Age Sex Donor Conditioning GVHD prophylaxis Disease status Collection time 1 48 M MUD/PB Ablative Bu/Cy MTX, ATG, Tacrolimus 2 58 M MUD/BM Ablative Bu/Flu MTX, ATG, Tacrolimus Remission Remission 6months 6 months 3 68 F MMUD/PB Non-ablative Bu/Flu MTX, Tacrolimus Remission 3 months 4 45 M MUD/PB Ablative Bu/Flu MTX, Tacrolimus Remission 5 months 5 68 F MSD/PB Non-ablative Bu/Flu MTX, Tacrolimus Remission 4 months 6 67 F MSD/PB Non-ablative Bu/Flu MTX, Tacrolimus Remission 3 months 7 59 M MSD/PB Non-ablative Bu/Flu MTX, Tacrolimus Relapse 4 months 8 52 M MSD/PB Ablative Bu/Flu MTX, Tacrolimus Relapse 6 months 9 64 F MUD/PB Non-ablative Bu/Flu MTX, Tacrolimus Relapse 5 months 1 53 F MUD/PB Ablativ Bu/Flu MTX, Tacrolimus Relapse 3 months M MSD/PB Ablative Bu/Cy MTX, Tacrolimus Relapse 2 months

12 PD-1 and TIM-3 are enhanced in patients with leukemia relapse % BTLA + CD4 CD8 % CD4 2B4 + CD8 % LAG3 + CD4 CD8 % CD16 + CD4 CD8 % TIM-3 + ** CD4 CD8 % CD4 PD-1 + CD8 % PD-1 high ** CD4 CD8 PD-1 + PD-1 high Relapse Remission Kong et al., Blood Cancer Journal, 215

13 PD-1 hi TIM-3 + cells associate with leukemia relapse post allsct A relapse CD4 CD8 remission relapse remission IV V VI TIM-3 I II III 3.4% 1.% 8.6%.4% PD-1 B 8 6 Ⅰ 8 6 Ⅱ Ⅲ Ⅳ Ⅴ Ⅵ * 2 15 * ** % * CD4 CD8 CD4 CD8 CD4 CD8 CD4 CD8 CD4 CD8 CD4 CD8 Relapse Remission Kong et al., Blood Cancer Journal, 215

14 PD-1 hi TIM-3 + cells produce less cytokines (CD4) Ⅳ 9.9% Ⅴ 14.9% Ⅵ 2.5% CD4 IV V VI I II III Ⅰ 4.1% Ⅱ 7.2% Ⅲ 3.% CD4 TIM-3 TNF-α Ⅳ 3.6% Ⅴ 7.4% Ⅵ.7% PD-1 CD4 Ⅰ 1.3% Ⅱ 2.3% Ⅲ.9% IFN-γ Kong et al., Blood Cancer Journal, 215

15 PD-1 hi TIM-3 + cells produce less cytokines (CD8) Ⅳ 8.9% Ⅴ 7.% Ⅵ 1.2% CD8 IV V VI I II III Ⅰ Ⅱ 1.8% 7.5% Ⅲ 1.4% CD8 TIM-3 TNF-α Ⅳ 2.8% Ⅴ 1.7% Ⅵ.2% PD-1 CD8 Ⅰ 3.7% Ⅱ 2.2% Ⅲ.2% IFN-γ IFN-γ Kong et al., Blood Cancer Journal, 215

16 Increase of PD-1 hi TIM-3 + cells predict leukemia relapse A TIM-3 CD4 Months after BM transplantation 1m 3m 4m 5m 6m relapse.5% 3.6% 4.8% 6.% 1.9% CD8.2% 1.9% 5.4% 7.2% 3.6% B PD-1 hi TIM3 + PD-1 C PD-1 hi TIM3 + % 1 relapse CD4 8 CD8 6 re-induction Months after BM transplatntation % 1 remission Months after BM transplatntation Kong et al., Blood Cancer Journal, 215

17 Blockade of PD-1 and TIM-3 show moderate increase of cytokine release Ctrl 1.9% 12.1% 6.1% CD4 PD-1 Ab 3.7% 14.% 7.1% Tim-3 Ab 2.4% 14.4% 7.1% PD-1 & Tim-3 Ab 4.1% 16.6% 7.4% IL-2 TNF-α IFN-γ Kong et al,, Unpublished dat

18 TIGIT (T cell immunoglobulin and immunoreceptor tyrosinebased inhibitory motif (ITIM) domain) Pauken KE, Wherry EJ. Cancer Cell. 214

19 TIGIT in Tumor immunity

20 TIGIT is elevated on CD8+ T cells from patients with leukemia relapse post allosct A CD8 + T cells TIGIT + Cell count 66.2% 8.5% 1.7% 36.9% TIGIT relapse remission % of TIGIT + cells in CD8 + T cells P=.352 relapse remission B CD4 + T cells TIGIT + Cell count 55.7% 39.9% 27.4% 21.9% TIGIT relapse remission % of TIGIT + cells in CD4 + T cells P=.166 relapse remission Kong etal., Unpublished data

21 TIGIT knockdown by sirna 45.5% 7.9% Ctrl TIGITsiRNA TIGIT MFI P=.383 NS sirna TIGIT sirna TIGIT Kong et al., Unpublished data

22 TIGIT knockdown enhanced cytokine release by CD8+ T cells from AML patients Non-specific sirna TIGIT sirna 6 P=.269 SSC 8.4% 16.4% TNF% 4 2 sirna: NS TIGIT TNF-α SSC 11.2% 17.5% IFN-γ IFN% P= sirna: NS TIGIT Kong et al., Unpublished data

23 Summary PD-1 hi TIM-3 + T cells are associated with leukemia relapse post allosct, and show functional impairment that consistent with exhaustion. PD-1 hi TIM-3 + Cells may have predictive value for leukemia relapse post allosct. Elevated TIGIT expression on CD8+ T cells correlates with leukemia relapse post allosct, TIGIT knockdown increased function of T cells from AML patients.

24 Conclusion T cell exhaustion associates with AML relapse post allosct. Combined blockade of inhibitory pathways involved in exhaustion may represent a effective leukemia therapeutic.

25 Acknowledgment Penn State Cancer Institute Laboratory Yaxian Kong M.D., Ph.D. Jianhong Zhang M.D. Liuluan Zhu Ph.D. Clinic David Claxton M.D. Christopher Ehmann M.D. Witold Rybka M.D. Todd Schell Ph.D. Penn State College of Medicine, Dept of Microbiology and Immunology Chinese American Hematologist and Oncologist Network Funding support ACS IRG The Kiesendahl Endowment Funding Start-up funds, Penn State College of Medicine