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Strategies for enhancing the efficacy of immunotherapy

Ned Waller MD, PhD, FACP

2Winship Cancer Institute | Emory University

Cancer Immunity PrinciplesTumors 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


Vaccines

CellularTherapies

AntibodiesTo TumorAssociatedAntigens

Immunological Modalities to Treat Cancer

4Winship Cancer Institute | Emory UniversitySchreiber 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


Distinction between 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 oncogeneicmutations/translocations in tumors, recognized by TILS- T cells extracted from the tumor microenvironment and expanded ex vivo.


Mutation Density Varies Across Different Cancers


• 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.


Naïve CD8+ T-cellCD45RA+ 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: pptakeof antigen from cancer cell

What Happens at the Beginning of Immune Responses?


Checkpoint Blockade and the Immunological Synapse

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


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

IFN-γ

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


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.


Long-term Survival of Patients with Renal Cell Cancer Treated with High-dose IL-2

Yang JC, et al. J Clin Oncol. 2006;24(35):5676-5583.


Three Different Mechanisms of Cellular Immunotherapy

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


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

Melinda Bachini2016

Lympho-depleting ChemotherapyCytoxan & Fludarabine

Tumor-specificT cells

Treatment of a patient using adoptive cell therapy with 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.

15Winship Cancer Institute | Emory UniversityTran E, et al. Science. 2014;344(6184):641-645.

Clinical Response and Persistence of Expanded T Cells in Vivo


Chimeric Antigen Receptor (CAR) T Cell Therapy

Signal 1 activation (CD3ζ)Signal 2 co-stimulation

2nd gen 4-1BB or CD283rd gen 4-1BB + CD28

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


Complete regression of DLBCL three months following CART therapy


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.


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.

9152530 9 6 1 1 0

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Events, n = 4Patients still at riskn =


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Healthy Untreated DLBCL Heavily-treated DLBCL

B. C.

A.

Total cellsCD27-CD28-depleted CD27-CD28-

Sytox blue

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FSCASS

CA

FSCW

FSC

HSytox blue

SSC

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Pre-sort

Post-sort

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Vasoactive intestinal polypeptide induces tolerogenic dendritic cells that limit inflammation

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

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


Structural model of VPAC1 receptor and docking of VIP

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


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

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


VIPhyb-treatment increased novel TCR-beta clones compared with donor and GvHDrecipients

DonorT cells

2.5%Oligoclonal

GvHDT cells

26%Oligoclonal

GvLT cells

22%Oligoclonal

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


Evolution of Immuno-oncology

Tum

or S

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ficity

Year

Off-

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s

1970 1980 1990 2000 2010 2020


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

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”

Paul Ehrlich 1854-1915

30Winship Cancer Institute | Emory [email protected]

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