Immunotransplant for Mantle Cell Lymphoma: A phase I/II study demonstrating amplification of tumor-reactive T cells Joshua Brody MD Division of Oncology Stanford University Medical Center
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CpG in situ vaccine (low grade lymphoma) immunotransplant vaccine vaccine-primed T cells autologous transplant immunotransplant (mantle cell lymphoma)
CpG-based vaccine for low-grade lymphoma B cell lymphoma TLR-9 CpG IFN CD137 lymphoma-reactive T cells radiation clinical response assessment CpG % change in distant lesions patient # 13 1 7 4 6 2 14 5 9 15 8 10 12 11 3 Brody JD et al., J Clin Oncol. 2010 Oct 1;28(28).
CpG-based vaccine induces anti-tumor T cells PRE 1.8% 0.5% CD8 CD45RO 8.8% POST 1.2% IFN CD137 CD8 T cell gate Brody JD et al., J Clin Oncol. 2010 Oct 1;28(28).
T-cell transfer into lymphodepleted recipients induces preferential T effector > T reg proliferation T cells CFSE-labeled T cells recipient foxp3 donor lymphodepleted recipient 16 8 4 2 1 CFSE Brody JD, et al., Blood. 2009 Jan 1;113(1).
Immunotransplant amplifies anti-tumor T cells induced by CpG-based vaccines 0.1% CpG in situ vaccine immunotransplant CpG transplant CpG ex vivo vaccine immunotransplant CpG-NHL transplant CD44 1.1% NHL vaccinated donor T cells lymphodepleted recipient 5.9% 0.1% day 0 CD44 IFN IFN CD8 T cell gate day 8 day 15 days post tumor challenge Brody JD, et al., Blood. 2009 Jan 1;113(1).
Immunotransplant for MCL: schema & endpoints MCL CpG vaccine vaccine-primed T cells biopsy induction chemotherapy autologous transplant immunotransplant primary endpoint: immune response IFN TNF IL2 MCL perforin granzyme CD137 tumor-reactive T cell
Immunotransplant for MCL: cohort
CpG-MCL vaccine: CpG differentially induces activation markers media media isotype-a HLA-DR isotype-p CD54 CD86 CpG CpG isotype-f HLA-ABC isotype-a CD40 CD80 fold-change with CpG
Immunotransplant for MCL: immune response Induction of tumor-reactive T cells occurs only after immunotransplant CD8 T cells prevaccine postvaccine 6.9% 9.6% post immunotransplant 25.6% pt 06 CD45RO granzyme B 1.8% 2.7% 10.6% perforin
8 6 4 2 0 Immunotransplant for MCL: immune response Induction of tumor-reactive T cells occurs only after immunotransplant 30 10 post-vaccine 10.0 24 8.0 18 6.0 12 4.0 6 2.0 patient # 0.0 CD137 IFNg 01 TNF a/b IL-2 CD137 IFNg TNF a/b IL-2 perforin granzyme B % tumor-reactive T cells (vs baseline) 10 09 08 06 05 03 01 granzyme B CD4 cells CD8 cells
8 6 4 2 0 Immunotransplant for MCL: immune response Induction of tumor-reactive T cells occurs only after immunotransplant 30 10 post-immunotransplant 10.0 24 8.0 18 6.0 12 4.0 6 2.0 patient # 0.0 CD137 IFNg 01 TNF a/b IL-2 CD137 IFNg TNF a/b IL-2 perforin granzyme B % tumor-reactive T cells (vs baseline) 10 09 08 06 05 03 01 granzyme B CD4 cells CD8 cells
Immunotransplant for MCL: preliminary results A proportion of tumor-reactive T cells are tumor-specific CD8 T cells prevaccine postvaccine post immunotransplant 2.8% 4.5% 31.4% MCL T cell tumor B cells granzyme CD45RO 2.8% 3.8% 21.2% B T cell normal B cells granzyme B
Tracking T cells with TCRβV high throughput sequencing: few T cell clones are amplified by CpG-MCL vaccine pre-vaccine post-vaccine
Tracking T cells with TCRβV high throughput sequencing: more T cell clones are amplified by immunotransplant post-vaccine post-immunotransplant
Tracking T cells with TCRβV high throughput sequencing: some T cell clones are amplified by in vitro tumor co-culture media co-culture tumor co-culture
TCRβV high throughput sequencing tumor-reactive T cells are amplified by immunotransplant in vitro tumor co-culture (log fold-change) fold change by immunotransplant p < 0.001 p < 0.001 in vivo before after immunotransplant (log-fold change)
Future Directions: 1) Assess whether immunotransplant improves the molecular remission rate compared to recent large studies of standard transplant for MCL: Pott C. et al., Blood. 2010 Apr 22;115(16):3215-23. Geisler CH, et al., Blood. 2008 Oct 1;112(7):2687-93. 2) Immunotransplant for: - aggressive NHL, PTCL, Myeloma 3) Non-ablative immunotransplant (e.g. fludarabine-based) for: - Hematologic: low-grade NHL, elderly MCL - Solid tumor: prostate CA melanoma
Thanks: Lymphoma Team: Ranjana Advani Holbrook Kohrt Transplant Team: Robert Negrin Kevin Sheehan BMT Lab Immune Studies Debra Czerwinski Etelka Gabriel High Throughput Sequencing Malek Faham Victoria Carlton (Sequenta Inc.) Biostatistics Phil Lavori Funding: Lymphoma Research Foundation NCI K99/R00 Pathway Award Mentorship: Ronald Levy Shoshana Levy PF-3512676 Pfizer Inc. All of the patients on: NCT00185965 NCT00880581 NCT00490529
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T reg -inducing tumors: inverse correlation with outcome gated on CD4 T cells gated on CD4 T cells pt #14 pt #13 pt #9 pt #3 pt #15 pt #11 foxp3 tumor media T reg inducers T reg non-inducers CD25 CD25 Progression Free Probability 0.0 0.2 0.4 0. 6 0.8 1.0 p = 0.0058 T reg inducers T reg non-inducers 20 40 60 80 100 120 weeks Brody JD et al., J Clin Oncol. 2010.