Strategies for enhancing the efficacy of immunotherapy Ned Waller - PowerPoint PPT Presentation

Strategies for enhancing the efficacy of immunotherapy Ned Waller MD, PhD, FACP 1

Cancer Immunity Principles Tumors express antigens recognized by immune cells • Aberrant expression of embryonic antigens. • Clonotypic neo-oncogenes (bcr/abl; B-cell idiotype). Over-expression of low expression antigens on tumors . • Tumor Surveillance: immune system limits cancer • Tumors may be eliminated before clinically detected. • Tumor development represents failure of immunity due to lack of antigen-specific responses or immune paralysis. • Patients with tumors may have tumor-specific memory T cells. Augmenting immunity causes cancer regression • Cytokine therapy- activate and expand T cells and NK cells • Monoclonal antibodies- direct cytotoxicity or antibody-dependent cellular cytotoxicity (ADCC) • Vaccine with to induce and amplify T-cell responses • Immune check-point blockade to reverse anergy of T cells • Infusion of antigen-specific T cells, NK cells Winship Cancer Institute | Emory University 2

Immunological Modalities to Treat Cancer Vaccines Cellular Antibodies Therapies To Tumor Associated Antigens Winship Cancer Institute | Emory University 3

Tumors that develop in an immuno-deficient host can be eliminated by a competent immune system Schreiber RD, et al. Science. 2011;331(6024):1565-1570. Winship Cancer Institute | Emory University 4

Distinction betw een tumor-associated antigens and tumor-specific antigens • Tumor associated: anti-CD20- Rituximab FDA approved in 11/26/1997 targets normal B-cells and CD20+ B-cell malignancies. • Tumor specific: Neo-antigens created by oncogeneic mutations/translocations in tumors, recognized by TILS- T cells extracted from the tumor microenvironment and expanded ex vivo. Winship Cancer Institute | Emory University 5

Mutation Density Varies Across Different Cancers Winship Cancer Institute | Emory University 6

• Driver mutations (red) cause an increase in the cell's fitness. • Mutations in housekeeper genes (pink) decrease a cell's fitness. • Passenger mutations (green) have no effect on fitness • Mutator mutations (yellow) leads to an increase in the cell mutation rate. Datta RS, et al. Evol Appl . 2013;6(1):20-33. Winship Cancer Institute | Emory University 7

What Happens at the Beginning of Immune Responses? Activated Apoptotic or Naïve CD8+ T-cell Necrotic Cancer Cytotoxic CD8+ CD45RA+ CCR7+ CD62L+ Cell T-cell CD45RO+ CD38+ CD57+ Antigen Processing and presentation of peptides on MHC I Antigen presentation by dendritic dell Cytolysis of Immature dendritic cell: pptake Cancer Cell of antigen from cancer cell Winship Cancer Institute | Emory University 8

Checkpoint Blockade and the Immunological Synapse Nirschl CJ, et al. Clin Cancer Res. 2013;19(18):4917-4924. Winship Cancer Institute | Emory University 9

Inhibition of antigen-specific T cells by PDL1 expression on tumors IFN- γ Pardoll D. Medocographia. 2014;36(3): 274-284. Winship Cancer Institute | Emory University 10

Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab McDermott DF, et al. J Clin Oncol. 2015;33(18):2013-2020. Winship Cancer Institute | Emory University 11

Long-term Survival of Patients w ith Renal Cell Cancer Treated w ith High-dose IL-2 Yang JC, et al. J Clin Oncol. 2006;24(35):5676-5583. Winship Cancer Institute | Emory University 12

Three Different Mechanisms of Cellular Immunotherapy Brody J, et al. J Clin Oncol. 2011;29(14):1864-1875. Winship Cancer Institute | Emory University 13

Treatment of a patient using adoptive cell therapy w ith TILs containing Vb22+ ERBB2IP mutation-reactive T cells Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Tumor-specific T cells Lympho-depleting Chemotherapy Cytoxan & Fludarabine Melinda Bachini 2016 Tran E, et al. Science. 2014;344(6184):641-645. Koh S, et al. J Hepatol . 2014;61(5):1175-1177. Winship Cancer Institute | Emory University 14

Clinical Response and Persistence of Expanded T Cells in Vivo Tran E, et al. Science. 2014;344(6184):641-645. Winship Cancer Institute | Emory University 15

Chimeric Antigen Receptor (CAR) T Cell Therapy Signal 1  activation (CD3ζ) Signal 2  co-stimulation 2 nd gen  4-1BB or CD28 3 rd gen  4-1BB + CD28 Jackson HJ, et al. Nat Rev Clin Oncol. 2016;13(6):370-383. Winship Cancer Institute | Emory University 16

Complete regression of DLBCL three months follow ing CART therapy Winship Cancer Institute | Emory University 17

DLBCL CAR T study: 59% Response Rate Patients (N = 51) a (95% CI, 44.2-72.4) Best overall response (CR + PR) 59% P < .0001 CR 43% PR 16% SD 12% PD 24% Overall response rate (CR + PR) 45% at 3 months CR 37% PR 8% a The interim analysis was preplanned to include the first 50 patients treated with CTL019 and followed for at least 3 months or discontinued early. CI, confidence interval; CR, complete remission; ORR, overall remission rate; PD, progressive disease; PR, partial remission; SD, stable disease. Winship Cancer Institute | Emory University 18

Duration of Response: 79% Relapse-free at 6 Months Duration of Response for patients in CR/PR (n = 30) 100 Probability of event free (%) 80 60 40 Events, n = 4 20 Patients still at risk n = 30 25 15 9 9 6 1 1 0 0 0 1 2 3 4 5 6 7 8 Time (months) • Median DOR not reached (median follow up, 6.4 months) • All responses at 3 months were ongoing at the time of cut-off – No responding patients went on to SCT • Median OS not reached (median follow-up, 2.8 months; max, 11.7 months) DOR, duration of response; OS, overall survival; SCT, stem cell transplant. Winship Cancer Institute | Emory University 19

A. Healthy Untreated DLBCL Heavily-treated DLBCL CD27 CD28 B. C. Winship Cancer Institute | Emory University 20

A. Pre-sort B. SSCA FSCH FSCA FSCW SSCA SSCA Sytox blue CD3 C. CD27-CD28- Total cells depleted CD27-CD28- CD27 CD28 SSCA Post-sort Sytox blue CD27 CD27 CD28 CD28

Vasoactive intestinal polypeptide induces tolerogenic dendritic cells that limit inflammation Waller EK. Blood. 2006;107(9):3423-3424. Winship Cancer Institute | Emory University 22

Gonzalez-Rey E, et al. Nat Rev Immunol. 2017;7(1):52-63. Winship Cancer Institute | Emory University 23

Structural model of VPAC1 receptor and docking of VIP Laburthe M, et al. Regul Pept. 2002;108(2-3):165-173. Winship Cancer Institute | Emory University 24

CD8 T-cells in the graft mediate the anti- leukemia activity of VIPhyb Li JM, et al. Cancer Res. 2016;76(23):6802-6815. Winship Cancer Institute | Emory University 25

VIPhyb-treatment increased novel TCR-beta clones compared w ith donor and GvHD recipients Donor T cells 2.5% Oligoclonal GvHD T cells 26% Oligoclonal GvL T cells 22% Oligoclonal Winship Cancer Institute | Emory University 26 Li JM, et al. Cancer Res. 2016;76(23):6802-6815.

Strategies for cancer immunotherapy • Improving the anti-cancer T cell repertoire • Vaccination with tumor-specific antigens • BMT CTN1401 DC-myeloma fusions • Dr. Al-Kadhimi myeloma peptide vaccine, MDSC depletion • Selecting non-anergic Tn and Tcm T cells for expansion • Ex vivo immunization with tumor-micro-vesicles • Optimization of antigen-specific T cell manufacturing • NK cell infusions with super-agonist IL15 • Bi-specific antibodies to target T cells to tumor • Combining Vaccines and check-point blockade • In vivo vaccination with chemo/XRT combined with check-point blockade, cytokines Winship Cancer Institute | Emory University 27

Evolution of Immuno-oncology Off-target effects Tumor Specificity Year 1970 1980 1990 2000 2010 2020 Winship Cancer Institute | Emory University 28

Paul Ehrlich, father of the “magic bullet” concept of chemotherapy and immunotherapy “For the sake of brevity, that combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor” Ehrlich and Morgenroth 1900. Berliner Paul Ehrlich 1854-1915 Klinische Wochenschrift. 2:196-204. Winship Cancer Institute | Emory University 29

ewaller@emory.edu Winship Cancer Institute | Emory University 30