Basics of Immuno-Oncology

Transcription

1 Basics of Immuno-Oncology Kyong Hwa Park MD, PhD Oncology/Hematology Korea University Hospital

2 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

3 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, (May 2009)

4 Science 25 March 2011

5 Cellular Immunity in Tumor microenvironment Mast cells NK cells M1 macrophage B cells T cells N1 neutrophils

6 Chronic Inflammation directs Th2 Immunity Primary tumor-derived factors Immune-mediated dormancy/elimination Successful metastatic outgrowth Cancer Res October 1, ; 5852

7 CD4+ Treg Immune Regulation Inhibitory cytokines Cytolysis of Teff Targeting DCs Competition Metabolic disruption Front. Immunol., 18 November 2013

8 Tumor Reprogramed Myeloid Cells Nature Reviews Immunology 12,

9 Immune Contexture

10 Immunity can Impact Disease Outcome: Role of Th1 CD4 + T Cells Th1 Signature: IFN Factors Predicting Outcome: Th1 T EM Central Dense >400 samples Pages et al, NEJM, samples J Galon et al, Science 2006 Galon et al, Science, 2006

11 Type, Density, and Location of Immune Cells J Galon et al, Science 2006

12 Association of Immune Cell Infiltration and Prognosis Fridman WH et al, Nat Rev Cancer 2012

13 다음중직접암세포살상기능이알려진면역세포는? 1) Naïve T cell 2) Dendritic cells 3) Foxp3+ CD4 T cells 4) CD8+ T cells 5) CD19+ B cells

14 Cancer Immunity Cycle Immunity 39, July 25, 2013

15 Stimulatory vs Inhibitory Factors in Cancer Immunity Cycle Immunity 39, July 25, 2013

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17 How to harness immune system to treat cancer? - Make TME Inflamed

18 Therapeutic Strategies to Harness Immune System

19 Effect of Anti-cancer Treatment on Immune Cells Indirect Effects Direct Effects Trends in Immunology April 2015, Vol. 36, No. 4, 2015

20 Malignant Melanoma

21 Role of RT in Induction of the Antitumor Immune Response 2013, JCI

22 Abscopal Effect by Radiotherapy N Engl J Med 2012;366:925-31

23 M/62, mrcc Rt RCC Radical nephrectomy, clear cell type 5년후 Recur: 1L Bevacizumab/IFNg 임상참여 2L Sunitinib: PD General condition and organ function - fair

24 What s your next treatment in Korea? 1) Everolimus 2) Pazopanib 3) Axitinib 4) High dose IL-2 5) Nivolumab

25 Cytokine therapy: HD IL-2 Clin Cancer Res; 21(3) February 1, 2015

26 Durable response & Life Prolongation Clin Cancer Res; 21(3) February 1, 2015

27 Cancer Vaccines Educating APCs properly

28 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 Dec; 20(0 3): S725 S730.

29 Combination Strategy: GVAX + PD-1/PD-L1 Ab Patients Mouse CD8+IFNɣ+ (Spleen, TIL) IFNɣ+ (Spleen, TIL) J Immunother Jan;38(1):1-11

30 Personalized Immunotherapy based on Tumor Neoantigen Neoantigen-specific and self-antigen specific T cells? Proteosomal processing? Correct identification of CD4 epitopes? In vitro detection of Ag processing and presentation? Schreiber et al, JCI Aug 2015

31 Dendritic Cell in Cancer Immunotherapy Nature Medicine 6, (2000)

32 DC Therapy for CRPC Study 1 Study 2 Provenge (n=341) Control (n=171) Provenge (n=82) Control (n=45) mos (m) HR (95%CI) (0.614, 0.979) (0.388, 0.884) p-value US FDA Approval! April

33 Disease Burden Intervention Based on Tumor Burden Vaccine Prevention Therapeutic Vaccines Alternative Strategies 1:10,000 T cells >1:10,000 T cells >1:100 T cells? Vaccines Adoptive Cell Therapy No Disease Microscopic Disease Established Disease

34 52세여자가우측발뒤꿈치에생긴점을주소로내원하여악성흑색종광범위절제및서혜부감시림프절생검술및절제후 3기암 (BRAF mutant) 으로진단되었다. 향후환자의경과를호전시키기위해적용할수있는가장적절한면역학적치료법은? 1) Nivolumab 2) CAR-T cell therapy 3) Vemurafenib 4) High dose IL-2 5) Cancer vaccine

35 Immune checkpoint Inhibitors a new Breakthrough

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37 Priming phase Effector phase PD-L1 CTLA-4 NEJM 366; June 28, 2012

38 History of anti-ctla Antibody AACR Cancer Progress Report 2014

39 Phase III Trial: Ipilimumab/gp100 vs Ipilimumab vs gp100 OS Ipilimumab/gp100 (n=403) Ipilimumab (n=137) mos (mon) vs gp100 HR 0.68 ( ) 0.66 ( ) P < vs Ipilim HR 1.04 ( ) P 0.76 US FDA Approval in March 2011 KFDA Approval in Dec 2014 ORR 5.7 % 11.0 % Gp100 (n=136) N Engl J Med 363;8 august 19, 2010

40 Mechanisms of PD-1 Expression Nature Immunology 14, (2013)

41 CD8+T cell Dynamics in Infection Acute Ag/functional memory Chronic Ag/ Exhaustion Trends in Immunology April 2015, Vol. 36, No. 4

42 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

43 PD-1 and T cell Dysfunction Jan, 2015, Nature Rev Immunology

44 Expression of PD-L 1 in Tumors Cancer types % PD L-1(+) Cancer types % PD L-1(+) Melanoma Ovarian cancer NSCLC Gastric carcinoma 42 Nasopharyngeal ca Esophageal ca 42 Glioblastoma/ mixed glioma 100 Pancreatic cancer 39 Colon 53 RCC HCC Breast cancer Urothelial cancer Lymphomas 17-94* Multiple myeloma 93 Leukemias Chen DS, Clin Cancer Res October 19, 2012.

45 Phase I Study of Single-Agent Anti PD-1 in Refractory Solid Tumors MDX-1106 (BMS /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) N/A MXR (1) CR (21+) PR(3+, 16+), 1MXR (1) Total CR, 2 PR, 2 MXR Brahmer JR, J Clin Oncol 28:

46 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

47 Dose of anti- PD-1 Ab NSCLC Objective response ORR Duration of response (M) Stable disease 24wk PFS rate at 24 wk NEJM June 28, 2012

48 NK Cells: Selected clinical trials with expanded allogeneic NK cells Front. Immunol., 03 June 2015

49 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. MDSC Treg TGFβ1 Cancer Immunol Res March ; 215

50 Adoptive T cell Therapy Genetically engineered TCR expressing T cells 2006 Science

51 Genetically engineered T-cell receptor recognizing NY-ESO-1 in Synovial Sarcoma T cells transduced with a retrovirus encoding a TCR against an HLA-A*0201 restricted NY-ESO-1 epitope Synovial sarcoma (n=18) Melanoma (n=20) Clinical Cancer Research, 21 (2015)

52 CAR T-Cell Therapy : Chimeric Antigen-Receptor based Therapy Clin Cancer Res; 18(10) May 15,

53 CAR T-Cell Therapy : Engineering Patients Immune Cells to Treat Their Cancers 53 Clin Cancer Res; 18(10) May 15, 2012

54 CAR-T cell Therapy in ALL N Engl J Med 2014; 371:

55 CAR-T cells Immunotherapy in Solid Cancers Target antigen? T cell expansion protocol Appropriate cell dose Patient conditioning Monitoring Elimination of CART 2016 AAAS, Riddell et al

56 Clinical Questions that you might have. Metastatic Cancer Remission PD-1 blockade Patient selection? Still immune response? Retreat? Anti-tumor immune response? How long treat? Combination approach?

57 Usual Pattern of Clinical Response Progressive Disease - 왜반응이없는가? - 항종양면역반응의부재 Stable Disease - 더효과를높일방법은없는가? - Immune signal 증폭방법은? Durable responses - 완전관해를이루는방법은? - 면역반응유지를모니터할방법은?

58 Rational Application of Immunotherapeutics Biomarkers - PD-1/PD-L1 expression - Mutational load Combination strategy Immune monitoring

59 MPDL3280A (anti-pd-l1) in Urothelial Cell Cancer Nature, 2014 Nov

60 PD-L1 Expression on TILs Nature, 2014 Nov

61 KEYNOTE-001: Phase Ib study of Pembrolizumab for the Treatment of NSCLC PD-L1 expression status by IHC: anti PD-L1 antibody clone 22C3 (Merck) Cells counted: neoplastic and intercalated mononuclear inflammatory cells N Engl J Med 2015;372:

62 PFS All patients All patients OS Prev Tx Prev Tx No Prev Tx No Prev Tx N Engl J Med 2015;372:

63 Randomised, phase 3 study of Nivolumab vs Docetaxel in advanced Squamous NSCLC after one prior Platinum-containing regimen Stage IIIB or IV squamous-cell NSCLC who had disease recurrence after one prior platinum-containing regimen R 1:1 N=272 Nivolumab 3 mg/kg q 2 wks Docetaxel 75mg/ m2 q 3wks Stratification: Prior use of paclitaxel therapy (yes vs. no) Geographic region (United States or Canada vs.europe vs. rest of the world [Argentina, Australia, Chile, Mexico, and Peru]). Primary endpoint: Overall survival N Engl J Med 2015;373:

64 9.2 mon vs 6.0 mon 3.5 mon vs 2.8 mon N Engl J Med 2015;373:

65 Percent membranous staining in 100 tumor cells. Archival or recent biopsy (Dako North America) used a rabbit monoclonal antihuman PD-L1 antibody (clone 28 8, Epitomics). N Engl J Med 2015;373:

66 Randomised, phase 3 study of Nivolumab vs Docetaxel in advanced non-squamous NSCLC after one prior Platinum-containing regimen Stage IIIB or IV nonsquamous-cell NSCLC who had progressed during or after platinum-based chemotherapy R 1:1 N=582 Nivolumab 3 mg/kg q 2 wks Docetaxel 75mg/ m2 q 3wks Stratification: Prior maintenance treatment (yes vs. no) Line of therapy (second line vs. third line). Primary endpoint: Overall survival N Engl J Med SEP2015; DOI: /NEJMoa

67 12.2 mon vs 9.4 mon 2.3 mon vs 4.2 mon N Engl J Med SEP2015; DOI: /NEJMoa

68 PD-L1 expression predicts Survival N Engl J Med SEP2015; DOI: /NEJMoa

69 PD-L1 as a Biomarker?: Issues Tumor heterogeneity Interval between biopsy and treatment Primary vs metastatic disease Ab and staining conditions Defining a positive result (cut-offs) - Immune cells vs tumor cells - Location of expression: intracellular vs surface vs stroma - Intensity, percent of positive cells - Distribution

70 Estimate of the Neoantigen Repertoire in Human Cancer. Somatic mutation frequencies (mutation burden) observed in exomes from 3,083 tumor normal pairs. Science 3 April 2015

71 PD-1 Blockade in mcrc N Eng J Med, Jun 2015

72 Prognosis Progression Free Survival for CRC Overall Survival for CRC How about the efficacy of PD-1 blockade in other cancers with MRD? Uterus, stomach, biliary tract, pancreas, ovary, prostate, and small intestine N Eng J Med, Jun 2015

73 Mutational Landscape of Melanoma according to the CTLA-4 blockade Response Mutational Load Survival in Discovery set Snyder A et al. N Engl J Med 2014;371:

74 Nonsynonymous mutation burden associated with clinical benefit of anti PD-1 therapy: NSCLC Mutational burden vs Response Smoking vs Prognosis Mutational burden vs Prognosis Science 3 April 2015

75 Mutation burden, clinical response, and factors contributing to mutation burden: NSCLC Science 3 April 2015

76 Neoantigen burden & Intratumoral Heterogeneity (ITH) Science MAR 2016

77 다음중항 PD-1/PD-L1 저해제치료로가장큰임상적 이득이가장적을것으로예상되는환자는? 1) Luminal A type 골전이만있는 32세유방암환자 2) Lynch syndrome으로진단받은 43세전이성대장암환자 3) 흡연력이있는 56세 4기폐편평상피세포암환자 4) BRCA1 돌연변이가있는 36세전이성삼중음성유방암환자 5) 50갑년의흡연력이있는 72세전이성방광암환자

78 Monotherapy might not be enough! Nanda et al, 2014 SABCS

79 Rational Application of Immunotherapeutics Biomarkers - PD-1/PD-L1 expression - Mutational load Combination strategy Immune monitoring

80 Therapeutic Strategies to Harness Immune System

81 Combination of anti-ctla4/anti-pd-1 in Untreated Melanoma Postow MA et al. N Engl J Med 2015;372:

82 Rational Application of Immunotherapeutics Biomarkers - PD-1/PD-L1 expression - Mutational load Combination strategy Immune monitoring

83 Strategies for Immune Monitoring Annu. Rev. Med :

84 CD8+ T cells with Pembrolizumab Response (n=22) Progression (n=24) Nature 515, (27 November 2014)

85 Proliferating CD8+ T cells in Regressing Tumors Nature 515, (27 November 2014)

86 Anything in blood? - Immune cell profiles - Cytokines - PBMC Immunomics

87 Baseline serum Cytokine score impacts OS in NSCLC Explorative analysis of CM-063 and 017 SQ-Cytoscore: IL-6, FRTN, CRP, MIP-16, Ip-10, IL-16, MICA, IL-1RA, MMP3, MIG, ICAM1, VDBP, vwf 2016 ASCO

88 Personalized Immunotherapy Strategy Patient Profiling Immune Monitoring Optimized Immunotherapy Protocol Computational Immunotherapy : Vaccine etc Briefings in Bioinformatics, 2015, 1 15

89 Future Oncology Treatment Paradigm Biomarkers supported by - Genomics - Seromics - Immunomics Personalized, Combined, Immunotherapy 89

90 Summary & Future Immunotherapy changed the paradigm of cancer therapy. CTLA-4 opened the door to age of immunotherapeutics for cancer. PD-1/PD-L1 antibodies harnessed new cancers to immunogenic ones. Identification of combinatorial strategy is a future direction. Development of predictive biomarkers is ongoing. More Understanding about tumor biology. Characterizing tumor immune microenvironment according to types and stages of tumors. Rational application of omics for personalized approach.

91 Research Cures Cancer!