Functional reprogramming of the tumor stroma by IL-12 Engineered T cells is required for anti-tumor immunity. Sid Kerkar, M.D.
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1 Functional reprogramming of the tumor stroma by IL-12 Engineered T cells is required for anti-tumor immunity Sid Kerkar, M.D.
2 Cancer Therapies Surgery Chemotherapy Radiation Emerging Cell Based Therapy
3 Mouse B16/Melanoma Model of Adoptive Cell Transfer Cell Transfer C57BL/6 or other hosts Pmel-1 CD8+ T cells Lymphodepleting (5Gy) Irradiation or C57/BL/6 CD8+ T cells transduced with Pmel TCR Tumor implantation Vaccine + IL-2 Blindly assess tumor growth and analyze immune response A tripartite regimen is effective: i) 1 million Pmel-1 CD8+ cells ii) 2 x 1 7 plaque-forming units of rvv encoding hgp1 iii) administration of high-dose IL-2: 6, IU BID for 3 days Overwijk WW et al. J Exp Med. 23 Aug 18;198(4):569-8
4 Tumor-Specific CD8+ T Cells Expressing Interleukin-12 eradicate established B16 melanomas with 1, cells and no IL-2 or Vaccine Kerkar SP et al. Cancer Res. 21 Sept. 1 st, 7;6725
5 Treatment with IL-12 engineered CD8+ T cells leads to increased tumor infiltration of adoptively transferred cells stably expressing IL-12 Kerkar SP et al. Cancer Res. 21 Sept. 1 st, 7;6725
6 IL-12 based anti-tumor immunity is dependent on endogenous factors Il12rb2 -/- cells 19 WT cells 18 Il12rb2 -/- cells 34 WT cells 87 Il12rb2 -/- cells 64 WT cells 86 CD8+ CD8+ 2 CD CD IL-12 IL-12 IFN- TNF- 3 3 Tumor Area (mm 2 ) 2 1 ** * Il12rb -/- cells (1e5) WT cells (1e5) Tumor Area (mm 2 ) * WT host WT cells (1e5) Il12rb -/- host WT cells (1e5)
7 IL-12 based anti-tumor immunity is dependent specifically on host bone marrow derived cells Donors Recipients Chimeras Donors Recipients Chimeras BM wt wt / wt BM wt Il-12r -/- / wt wt Il-12r -/- wt / Il-12r -/- Il-12r -/- Il-12r -/- Il-12r -/- / Il-12r -/- 3 3 Tumor area (mm 2 ) * wt / wt Il-12r -/- / wt Tumor area (mm 2 ) * Il-12r -/- / Il-12r -/- wt / Il-12r -/-
8 IFN- expression and sensitization through host cells is critical for successful treatment V -13 Control Double TD % 3% WT cells V -13 Control Double TD % 25% IFN- -/- cells Tumor area (mm 2 ) IL WT Host P-TCR/IL-12 (IFN- -/- cells) P-TCR/IL-12 (WT cells) IFN- -/- Host P-TCR/IL-12 (IFN- -/- cells) P-TCR/IL-12 (WT cells) Tumor area (mm 2 ) IL * (IFN- R -/- Host) (WT Host) (IFN- R -/- Host) (WT Host)
9 Host NK, T and B cells are not necessary for tumor rejection Tumor area (mm 2 ) WT host NT RAG -/- host NT Tumor area (mm 2 ) NT (WT) NT (WT) + anti-nk1.1 ab (WT-h) + anti-nk1.1 ab (RAG -/- h) + anti-nk1.1 ab
10 Majority of cells expressing IL-12R 2 within the tumor are CD11b+ myeloid derived cells % 8 PI IL-12R CD11b P-Mock SSC-A % 5K 1K 15K 2K 25K SSC-A %51.3 5K 1K 15K 2K 25K FSC-A FSC-A PI-, CD3-, NK1.1-, B22- CD11b+
11 CD11b+ Myeloid Cells within tumors of IL-12 treated mice have higher expression of FAS (CD95) P-Mock % % FAS * CD11b % of CD11b cells + for FAS Relative mrna of CD11b+ cells (/P-Mock) FAS L FADD FAS BID FADD P-Mock
12 Adoptively transferred CD8+ T cells within the tumor have high FASL expression Pmel B16 Tumor IL 12 CD8 FASL CD8 Thy1.1 CD8 FASL Pmel Thy1.1+ cells expressing IL-12 were transferred into C56/BL6 mice
13 Summary Small numbers of tumor specific T cells overproducing IL-12 within the tumor microenvironment can eradicate large established tumors Anti-tumor immunity is dependant on IL-12 and IFN- dependent sensitization of host bone marrow derived myeloid cells IL-12 engineered T cells induce functional changes in the myeloid population residing within tumors Anti-tumor immunity is largely dependent on the ability of endogenous cells to cross-present tumor antigens in vivo
14 Clinical Applicability Clinical grade inducible vector designed by Ling Zhang and Richard Morgan Phase I/II Study of Metastatic Melanoma Using Lymphodepleting Conditioning Followed by Infusion of CD8 Enriched Tumor Infiltrating Lymphocytes Genetically Engineered to Express IL-12 Principal Investigator Steven A. Rosenberg, M.D. Ph.D.
15 Acknowledgments Robert Reger Pawel Muranski Zhiya Yu Dhana Chinnasamy Andrea Boni Andrew Kaiser Luis Sanchez-Perez Doug Palmer Luca Gattinoni Christopher Klebanoff Yun Ji STEVEN A. ROSENBERG Romina Goldszmid NICHOLAS P. RESTIFO GIORGIO TRINCHIERI
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competes with 20S proteasome for binding with C/EBP leading to its stabilization and Relative mrna levels Supplement Figure S1. Real Time PCR analysis of mrna levels of C/EBPα and PU.1 in wild type (WT)
T cell therapies are T memory stem cells the answer?
Editorial Page 1 of 5 T cell therapies are T memory stem cells the answer? Jacqueline K. Flynn 1,2,3, Paul R. Gorry 1,2,3,4 1 School of Applied Sciences and Program in Metabolism, Exercise and Disease,
Nature Immunology: doi: /ni Supplementary Figure 1. Cellularity of leukocytes and their progenitors in naive wild-type and Spp1 / mice.
Supplementary Figure 1 Cellularity of leukocytes and their progenitors in naive wild-type and Spp1 / mice. (a, b) Gating strategies for differentiated cells including PMN (CD11b + Ly6G hi and CD11b + Ly6G