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

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

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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

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Strategies for enhancing the efficacy

  • f immunotherapy

Ned Waller MD, PhD, FACP

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2 Winship Cancer Institute | Emory University

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
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Vaccines Cellular Therapies Antibodies To Tumor Associated Antigens

Immunological Modalities to Treat Cancer

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Schreiber RD, et al. Science. 2011;331(6024):1565-1570.

Tumors that develop in an immuno-deficient host can be eliminated by a competent immune system

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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.

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Mutation Density Varies Across Different Cancers

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  • 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
  • n fitness
  • Mutator mutations (yellow) leads to an

increase in the cell mutation rate.

Datta RS, et al. Evol Appl. 2013;6(1):20-33.

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Naïve CD8+ T-cell CD45RA+ CCR7+ CD62L+ Apoptotic or Necrotic Cancer Cell Antigen Processing and presentation of peptides on MHC I Activated Cytotoxic CD8+ T-cell CD45RO+ CD38+ CD57+ Antigen presentation by dendritic dell Cytolysis of Cancer Cell Immature dendritic cell: pptake

  • f antigen from cancer cell

What Happens at the Beginning of Immune Responses?

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Checkpoint Blockade and the Immunological Synapse

Nirschl CJ, et al. Clin Cancer Res. 2013;19(18):4917-4924.

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Inhibition of antigen-specific T cells by PDL1 expression on tumors

IFN-γ

Pardoll D. Medocographia. 2014;36(3): 274-284.

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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.

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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.

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Three Different Mechanisms of Cellular Immunotherapy

Brody J, et al. J Clin Oncol. 2011;29(14):1864-1875.

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Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Melinda Bachini 2016

Lympho-depleting Chemotherapy Cytoxan & Fludarabine

Tumor-specific T cells

Treatment of a patient using adoptive cell therapy w ith TILs containing Vb22+ ERBB2IP mutation-reactive T cells

Tran E, et al. Science. 2014;344(6184):641-645. Koh S, et al. J Hepatol. 2014;61(5):1175-1177.

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Tran E, et al. Science. 2014;344(6184):641-645.

Clinical Response and Persistence of Expanded T Cells in Vivo

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Chimeric Antigen Receptor (CAR) T Cell Therapy

Signal 1 activation (CD3ζ) Signal 2 co-stimulation 2nd gen 4-1BB or CD28 3rd gen 4-1BB + CD28

Jackson HJ, et al. Nat Rev Clin Oncol. 2016;13(6):370-383.

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Complete regression of DLBCL three months follow ing CART therapy

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DLBCL CAR T study: 59% Response Rate

Patients (N = 51)a Best overall response (CR + PR) 59% (95% CI, 44.2-72.4) P < .0001 CR 43% PR 16% SD 12% PD 24% Overall response rate (CR + PR) at 3 months 45% 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.

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Duration of Response: 79% Relapse-free at 6 Months

Duration of Response for patients in CR/PR (n = 30)

  • 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.

9 15 25 30 9 6 1 1 100 80 60 40 20

Time (months) Probability of event free (%)

4 1 2 3 5 6 7 8 Events, n = 4 Patients still at risk n =

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A. CD27 CD28 Healthy Untreated DLBCL Heavily-treated DLBCL B. C.

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A.

Total cells CD27-CD28- depleted CD27-CD28- Sytox blue

C.

FSCA SSCA FSCW FSCH Sytox blue SSCA CD3 SSCA CD28 CD27 CD28 CD27 CD28 CD27 Pre-sort Post-sort SSCA

B.

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Vasoactive intestinal polypeptide induces tolerogenic dendritic cells that limit inflammation

Waller EK. Blood. 2006;107(9):3423-3424.

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Gonzalez-Rey E, et al. Nat Rev Immunol. 2017;7(1):52-63.

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Structural model of VPAC1 receptor and docking of VIP

Laburthe M, et al. Regul Pept. 2002;108(2-3):165-173.

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CD8 T-cells in the graft mediate the anti- leukemia activity of VIPhyb

Li JM, et al. Cancer Res. 2016;76(23):6802-6815.

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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

Li JM, et al. Cancer Res. 2016;76(23):6802-6815.

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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
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Evolution of Immuno-oncology

Tumor Specificity Year Off-target effects 1970 1980 1990 2000 2010 2020

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Ehrlich and Morgenroth 1900. Berliner Klinische Wochenschrift. 2:196-204.

Paul Ehrlich, father of the “magic bullet” concept

  • f 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”

Paul Ehrlich 1854-1915

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ewaller@emory.edu