Engineered T cells: Next-generation cancer immunotherapy
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1 Engineered T cells: Next-generation cancer immunotherapy Rahul Purwar, Assistant Professor Department of Biosciences & Bioengineering Indian Institute of Technology Bombay (IIT Bombay) Mumbai, India,
2 Outline Introduction Adoptive T cell therapy: Engineered CAR-T cells Review of recent clinical trials Challenges of CAR T cell therapy Results T cell subsets: Th17 and Th9 cells in cancer immunotherapy Summary Adoptive T cell therapy: what we learnt and what we should do next
3 Overview: Adoptive T cell therapy 1.Isolation of TILs or tumor specific T-cells from blood 2.Expand and activate T-cells ex vivo 3.Infuse the "boosted" T-cells into the patient. Target therapy with Tumor specific T cells Cancer: Melanoma Autologous tumor infiltrating lymphocytes (TILs); Live drug Advantages High response rate (>50%), Long-term remission, Less toxic & gentler to the patient Limitation: Extraction of TILs, Cell manufacturing Possible alternate T cell Engineering (CAR-T cells) Rosenberg SA & Dudley ME 2009 Current Opinion of Immunology
4 Adoptive T cell therapy: CAR-T cells CAR-T cells (Chimeric antigen receptor-t cells0 T cells transduced with tumor-specific CAR CAR: Single fusion molecule with antigen specificity plus signaling domain Three types of CAR: First/second/generations Based on co-stimulatory receptors Cancer: Solid tumor & hematological malignancies Antigen specific domain Advantages of CAR T cells Live drug Tumor recognition independent of HLA (no HLA typing needed) Multiple antitumor immunomodulators can be engineered Target variety of antigens (protein, carbohydrate, glycolipid) Maus M V et al. Blood 2014;123:
5 Clinical significance of CAR-T cells Target CAR Cancer Objective response CD19 CAR:CD28-CD3ζ Lymphoma and CLL CAR:CD137-CD3ζ ALL 2CR CAR:CD28-CD3ζ ALL 5CR N=7:1CR, 5 PR & 1SD CEA CAR-CD3ζ (1 st gen) Colorectal & breast GD2 CAR-CD3ζ (1 st gen) Neuroblastoma N=19: 3CR ERBB2 CD20 CAR:CD137-CD28- NHL N=3: 1PR, 2NED CD3ζ CAR:CD28-CD137- CD3ζ Colorectal cancer N=7: minor responses in two patients N=1, patient died Kershaw et. al Nature Reviews cancer
6 Toxicities On target/off tumor toxicities Metastatic colon cancer patient died after 5 days of infusion of ERBB2+CAR-T cells Low levels of ERBB2 express on lung epithelium (lung tox) Renal cell carcinoma: 5/11 patients developed liver toxicity Cytokine syndrome Challenges of CAR-T cells Elevated levels of pro-inflammatory cytokines Treatable by anti-il-6mab and steroids
7 Determinants of successful ACT: CAR-T cells Tumor target Target antigen is critical determinant for efficacy & safety Ideal target uniquely express on tumor cells or on cells which are not essential for survival Efficacy & Long-term persistence Subtypes of CD4+T cells (Th1, Th2, Th17, Th9 cells), CD8+T cells naïve, central memory; long-term effector; active but short lived Trafficking of CAR T cells to tumor Expression of addressins Route of CAR-T cell infusion Intra-tumoral/intravenous Optimal co-stimulation of T cells Patient conditioning before ACT Reduced-intensity or nonmyeloablative Increased intensity myelo ablative
8 Outline Introduction Adoptive T cell therapy: focus on engineered CAR-T cells Overview of current & investigational CAR therapies Challenges of CAR T cell therapy Results Roles of T-helper cell subsets in cancer immunotherapy Summary ` Adoptive T cell therapy: what we learnt and what we should do next
9 Adoptive T cell therapy: Right T cell population? CD4+ T cells Zou W & Restifo NP Nature Reviews Immunology 2010 IL23R
10 Role of Th17 cells in tumor immunity is controversial Pro-tumor: - enhances vascularization/angiogenesis -promotes metastasis - promotes growth Langowski et al, Nature 2006; Murugayen 2011 J.Immunol; Wang et al. J.Exp.Med 2009 Anti-tumor: -enhances tumor immunity by promoting CD8+T cell and DC function Martin-Orcazzo et al Immunity 2010
11 Tumor growth suppression in ROR -/-mice (Th17 cell deficient) Tumor volum me (mm 3 ) Melanoma tumor growth RORγ+/+chimeric mice RORγ-/-chimeric mice ** *** Days after tumor induction % of mice (s survival) Survival of tumor bearing host RORγ+/+ chimeric mice RORγ-/- chimeric mice Days after tumor induction Abrogation of Th17 pathways promotes anti-tumor immune responses
12 Gene-expression analysis: ROR -/- CD4+T cells Slc15a2 Robo3 Robo3 Gzmc Il9 Abp1 Gzmb Foxn4 Ak1 Il28ra Zfp423 S100a4 Rhod Ckmt1 Lgr4 Apobec2 Cckbr Galntl4 Phlda3 Pgr Slc2a4 Ms4a4b Il1f9 Ly6d Mal2 Id4 Gpr81 Penk Ptger3 Psrc1 Penk Ms4a4b Il12b Ebf4 Gzmd Spib Mmp13 Serpinb9 Serpinb6b Il10 Ifng Il4 Eomes Tbx21 (Tbet) Il17re Il17f Ccr2 Malat1 Serpinb1a Pkib Ccl24 Col16a1 Ramp1 Itga7 Serpinb2 Il17a Col4a2 Serpinb2 Cysltr1 Selenbp2 Selenbp1 Il23r Num mbers of IL9+ve cells (%) ** WT RORγ-/- IL-17f IL-17a IL-9 IL-23r Increased IL-9 expression in RORγ-/-CD4+T cells CD4+T cells differentiated under Th17 conditions (RORγ-/- / RORγ +/+Fold change) Th17 genes
13 Treatment with exogenous ril-9 suppresses tumor growth Efficacy study plan Day 0 Subq B16F10 (1x10 5 /100 µl) LLC (1x10 5 /100 µl) Day 0 onwards ril µg/mouse (i.p.), Every alternate day Results Delayed tumor growth in IL-9 treated group Follow tumor development (3x/week) IL-9 mediated anti-tumor effects are not limited to melanoma tumor model Tumor volume (mm 3) Tumor volume (mm 3 ) Melanoma (B16F10) Control ril-9 treated * control Lung carcinoma ril-9 treated (LLC) Days after tumor induction *
14 Effects of ril-9 on melanoma tumor growth in Rag1-/-mice (T cell and B cell deficient host) 1,500 Control Tumor vo olume (mm 3 ) 1, ** ril-9 treated Time after tumor induction (d) IL-9 mediated tumor growth suppression is independent of T cells and B cells
15 Effects of ril-9 on tumor tumor growth in mast cell-/-mice Melanoma (B16F10) Lung carcinoma (LLC) Tumor volu ume (mm 3 ) Control 1500 ril-9 treated ns Tumor volu ume (mm 3) Days after tumor induction control ril-9 treated IL-9 mediated tumor growth suppression is dependent of mast cells
16 Engineering Th9 cells: TAA specific Tumor model Engineer tumor specific Th9 cells OT2 TCR transgenic mice (CD4 cells recognize ova) TGFβ+ IL-4 Th9 Naïve OT2 Normal WT or Rag1-/- CD4+CD25- CD62L+ TGFβ+ IL-6 Th17 B16F10-Ova cells Follow tumor development Generation of Ovalbumin expressing B16 tumor cells (Lentiviral method)
17 Treatment with Th9 cells suppresses tumor growth Immunocompetent host (Wild type) Tumor volume (mm 3 ) 2000 no T cells Th17 Th9 *** Days after tumor induction No T cells Th17 cells Th9 cells
18 Th9 cell therapy: efficacy studies in immunodeficient host Rag1-/-(T cells and B cells deficient) Tumor volume (mm 3) no T cells Th0 cells Th9 Th9 plus a-il-9 ** * Days after tumor induction Th9 cells suppresses tumor growth independent of T cell and B cell presence
19 Mechanism of anti-tumor effects of Th9 cells Effects of Th9 cells on CD8+T cells (OT-1 cells) proliferation No Th cells 90% CFSE labeled OT1-CD8-T cells irradiated B16- Ova cells + ± OT2-Th0 or OT2- Th9 cells 3 days Evaluation of OT1-CD8-T cells by flow cytometry +Th0 cells 45% Presence of Th9 cells promotes the OT1- CD8-T cells proliferation. counts + Th9 cells 5% OT1 cells: ovalbumin specific CD8+T cells CFSE: Carboxyfluorescein succinimidyl ester CFSE
20 Mechanism of anti-tumor effects of Th9 cells Examining Cytotoxic activity of Th9 cells 5mM CFSE labeled B16F10-ova cells mm CFSE labeled EL-4 cells No Th cells EL-4 B16-Ova ± OT2-Th0 or OT2-Th9 36 h. Tumor cell lysis was measured by flow cytometry. Th9 cells lyse tumor cells in antigen/ target dependent manner counts + Th0 cells (25:1) Th9 cells (25:1) Target cells: B16-Ova B16 ova specific Th cells: OT2-Th cells CFSE
21 What is the relevance of these findings in human? Translational research
22 Th9 cells are present in human skin and blood Th9 cells IL-9 PU.1 Skin Blood Gate on CD4+IFNγ-IL-4- IL-17 CD4+IL-9+ +IFNg-IL-4-IL-17- (%) * * Blood Skin T cells from metastasis IL-9 Healthy subjects Melanoma Th9 cells are not just a murine phenomenon
23 Summary CAR-T cells T cells transduced with tumor-specific Chimeric Antigen Receptor (CAR) Tumor recognition independent of HLA (no HLA typing needed) Target: variety of tumor antigens (protein, carbohydrate, glycolipid) High response rate (up to 88%): pre-clinical and clinical findings Limitation of CAR-T cells Toxicities On target/off tumor toxicities Cytokine syndrome Tumor microenvironment Presence of MDSCs & Treg in tumor Immunosuppressive agents Results & Conclusion IL-9 is a novel anti-tumor cytokine and anti-tumor effects are mediated via mast cells Th9 cells are the most superior anti-tumor Th cells Th9 cells exists in human: not just murine phenomenon Strategies that promotes IL-9 production will be a critical for the development of robust treatment for melanoma and lung carcinoma.
24 Acknowledgement Laboratory members at IIT Bombay Richa Agarwal Mukti Vats Farha Memon Sathya Atish Department of Dermatology, Brigham & Women s Hospital (BWH) Thomas S Kupper Department of Neurology, BWH Vijay K Kuchroo Wassim Elymann Sheng Xiao National Institute of Health (NIH/NIEHS) Anton J Jetten Hong Soon Kang!!Thanks a lot!!
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