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Basics of Immuno-Oncology AACR Cancer Progress Report 2014 Phase III Trial: Ipilimumab/gp100 vs Ipilimumab

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  • Basics of Immuno-Oncology

    2016. 6. 25

    Kyong Hwa Park MD, PhD

    Oncology/Hematology

    Korea University Hospital

  • Contents

    • Immune microenvironment in cancer

    • Immunologic therapeutics in Oncology

    - Cytokines - Vaccines

    - Immune checkpoint Inhibitors – a new breakthrough

    - Cell-based treatment

    • Rational Application of Immunotherapeutics - Biomarkers - Combination strategy

    - Immune monitoring

    • Summary & Future directions

  • Coley’s Toxins

    • William Coley (New York surgeon) began intratumoral injections of live or inactivated bacteria (1891)

    • Stimulate antibacterial phagocytes that might kill bystander tumour cells

    Nature Reviews Cancer 9, 361-371 (May 2009)

  • Science 25 March 2011

  • Cellular Immunity in Tumor microenvironment

    Mast cells

    T cells N1 neutrophils

    M1 macrophage

    NK cells

    B cells

  • Chronic Inflammation directs Th2 Immunity

    Primary tumor-derived factors

    Successful metastatic outgrowth

    Immune-mediated dormancy/Elimination

    Cancer Res October 1, 2013 73; 5852

  • CD4+ Treg Immune Regulation

    Front. Immunol., 18 November 2013

    Targeting DCs

    Metabolic disruption

    Competition

    Cytolysis of Teff Inhibitory cytokines

  • Tumor Reprogramed Myeloid Cells

    Nature Reviews Immunology 12, 253-268

  • Immune Contexture

  • Pages et al, NEJM, 2005

    Immunity can Impact Disease Outcome: Role of Th1 CD4+ T Cells

    Galon et al, Science, 2006

    Factors Predicting Outcome:

    Th1 TEM

    Central Dense

    >400 samples

    75 samples

    Th1 Signature: IFN

    J Galon et al, Science 2006

  • Type, Density, and Location of Immune Cells

    J Galon et al, Science 2006

  • Association of Immune Cell Infiltration and Prognosis

    Fridman WH et al, Nat Rev Cancer 2012

  • 다음 중 직접 암세포 살상 기능이 알려진 면역세포는?

    1) Naïve T cell

    2) Dendritic cells

    3) Foxp3+ CD4 T cells

    4) CD8+ T cells

    5) CD19+ B cells

  • Cancer Immunity Cycle

    Immunity 39, July 25, 2013

  • Stimulatory vs Inhibitory Factors in Cancer Immunity Cycle

    Immunity 39, July 25, 2013

  • How to harness immune system to treat cancer?

    - Make TME ‘Inflamed’

  • Therapeutic Strategies to Harness Immune System

  • Effect of Anti-cancer Treatment on Immune Cells

    Trends in Immunology April 2015, Vol. 36, No. 4, 2015

    Indirect Effects Direct Effects

  • Malignant Melanoma

  • Role of RT in Induction of the Antitumor Immune Response

    2013, JCI

  • Abscopal Effect by Radiotherapy

    N Engl J Med 2012;366:925-31

  • M/62, mRCC

    • Rt RCC – Radical nephrectomy, clear cell type

    • 5년 후 Recur: 1L Bevacizumab/IFNg 임상참여

    • 2L Sunitinib: PD

    • General condition and organ function - fair

  • What’s your next treatment in Korea?

    1) Everolimus

    2) Pazopanib

    3) Axitinib

    4) High dose IL-2

    5) Nivolumab

  • Cytokine therapy: HD IL-2

    Clin Cancer Res; 21(3) February 1, 2015

  • Durable response & Life Prolongation

    Clin Cancer Res; 21(3) February 1, 2015

  • Cancer Vaccines

    Educating APCs properly

  • GVAX Probably Improves PDA Patients

    • GVAX: a human whole cell granulocyte macrophage colony-stimulating factor (GM-CSF) secreting pancreatic cancer vaccine

    • Phase II Study in patients received CCRT after R0/R1 resection for PDA

    Ann Surg Oncol. 2013 Dec; 20(0 3): S725–S730.

  • Combination Strategy: GVAX + PD-1/PD-L1 Ab

    J Immunother. 2015 Jan;38(1):1-11

    Patients

    Mouse CD8+IFNɣ+ (Spleen, TIL) IFNɣ+ (Spleen, TIL)

  • Personalized Immunotherapy based on Tumor Neoantigen

    Schreiber et al, JCI Aug 2015

     Neoantigen-specific and self-antigen–specific T cells?  Proteosomal processing?  Correct identification of CD4 epitopes?  In vitro detection of Ag processing and presentation?

  • Dendritic Cell in Cancer Immunotherapy

    Nature Medicine 6, 966 - 968 (2000)

  • DC Therapy for CRPC Study 1 Study 2

    Provenge (n=341) Control (n=171) Provenge (n=82) Control (n=45)

    mOS (m) 25.8 21.7 25.9 21.4

    HR (95%CI) 0.775 (0.614, 0.979) 0.586 (0.388, 0.884)

    p-value 0.032 0.010

    www.dendreon.com

    US FDA Approval! April 2010

  • Intervention Based on Tumor Burden

     1:10,000 T cells >1:10,000 T cells >1:100 T cells?

    Vaccine Prevention

    Therapeutic Vaccines

    Alternative Strategies

    D is

    e as

    e B

    u rd

    e n

    Vaccines Adoptive Cell Therapy

    No Disease Microscopic Disease Established Disease

  • 52세 여자가 우측 발뒤꿈치에 생긴 점을 주소로 내원하여 악성 흑색종 광

    범위 절제 및 서혜부 감시 림프절 생검술 및 절제 후 3기암 (BRAF mutant)

    으로 진단되었다.

    향후 환자의 경과를 호전시키기 위해 적용할 수 있는 가장 적절한 면역학

    적 치료법은?

    1) Nivolumab

    2) CAR-T cell therapy

    3) Vemurafenib

    4) High dose IL-2

    5) Cancer vaccine

  • Immune checkpoint Inhibitors – a new Breakthrough

  • Priming phase Effector phase

    CTLA-4

    PD-L1

    NEJM 366;26 2518 June 28, 2012

  • History of anti-CTLA Antibody

    AACR Cancer Progress Report 2014

  • Phase III Trial: Ipilimumab/gp100 vs Ipilimumab vs gp100

    OS Ipilimumab/gp100 (n=403)

    Ipilimumab (n=137)

    Gp100 (n=136)

    mOS (mon) 10.0 10.1 6.4

    vs gp100 HR 0.68 (0.55–0.85) 0.66 (0.51–0.87)

    P

  • Mechanisms of PD-1 Expression

    Nature Immunology 14, 1212–1218 (2013)

  • CD8+T cell Dynamics in Infection

    Trends in Immunology April 2015, Vol. 36, No. 4

    Acute Ag/functional memory Chronic Ag/ Exhaustion

  • PD-1/PD-L1: Exhaustion of T cells

    1) Antagonizing TCR signaling

    2) Decreased survival, proliferation, altered metabolism

    3) Reduced proliferation via RAS path

    4) Altered transcription

    5) Altered T cell motility

    Trends in Immunology April 2015, Vol. 36, No. 4

  • PD-1 and T cell Dysfunction

    Jan, 2015, Nature Rev Immunology

  • Expression of PD-L 1 in Tumors

    Cancer types % PD L-1(+) Cancer types % PD L-1(+)

    Melanoma 40-100 Ovarian cancer 33-80

    NSCLC 35-95 Gastric carcinoma 42

    Nasopharyngeal ca 68-100 Esophageal ca 42

    Glioblastoma/ mixed glioma

    100 Pancreatic cancer 39

    Colon 53 RCC 15-24

    HCC 45-93 Breast cancer 31-34

    Urothelial cancer 28-100 Lymphomas 17-94*

    Multiple myeloma 93 Leukemias 11-42

    Chen DS, Clin Cancer Res October 19, 2012.

  • Phase I Study of Single-Agent Anti–PD-1 in Refractory Solid Tumors

    • MDX-1106 (BMS-936558/ONO-4538)

    : fully human IgG4 mAb specific for humanPD-1

    • Patients (n=39): CRC(14), Melanoma(10), NSCLC(8), Prostate(6), RCC(1)

    Dose (mg/kg) No. of patients

    Total No. of Doses Best Response (Duration in month) 1 2 3 5 11

    0.3 6 6 0 0 0 0 N/A

    1 6 3 1 1 1 0 1 MXR (1)

    3 6 3 0 2 1 0 1 CR (21+)

    10 21 15 1 4 0 1 2 PR(3+, 16+), 1MXR (1)

    Total 39 27 2 7 2 1 1 CR, 2 PR, 2 MXR

    Brahmer JR, J Clin Oncol 28:3167-3175. 2010

  • Expanded Phase I Study

    Dose of anti- PD-1 Ab

    Objective response

    ORR Duration of

    response Stable disease ≥

    24wk PFS rate at

    24 wk

    Melanoma

    NEJM June 28, 2012

  • Dose of anti- PD-1 Ab

    Objective response

    ORR Duration of

    response (M) Stable disease ≥

    24wk PFS rate at

    24 wk

    NSCLC

    NEJM June 28, 2012

  • NK Cells: Selected clinical trials with expanded allogeneic NK cells

    Front. Immunol., 03 June 2015

  • Phase I : Random Healthy Donor–Derived Allo-NK Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors

    • Maximum dose (3 × 107 cells/kg, triple infusion): tolerable without significant AE

    • Of 17 evaluable patients, 8 patients (47.1%) SD, 9 (52.9%) PD.

    Cancer Immunol Res March 2016 4; 215

    Treg TGFβ1

    MDSC

  • Adopt