Micro 204 Tumor Immunology.
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1 Micro 204 Tumor Immunology
2 Part 1 Immunosurveillance & Immunoediting Tumor Antigens - definition & discovery Part 2 Cancer Immunotherapy
3 Immunological Surveillance Ehrlich, Burnet & Thomas Paul Ehrlich (1909) Concept of cancer immunosurveillance. Predicted that cancer would occur at incredible frequency if host defenses did not prevent the outgrowth of continuously arising cancer cells Lewis Thomas (1957) primary function of cellular immunity.is to protect from neoplastic disease Macfarland Burnet (1957) It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provide an effective immunological reaction with regression of this tumor and no clinical hint of its existence
4 Evidence for immune surveillance in humans Increased incidence of EBV+ B cell lymphomas in transplant patients treated with immunosuppressive drugs Increased incidence of Kaposi s sarcoma & EBV+ B cell lymphomas in AIDS patients Gastric cancer associated with H. pylori infection Cervical cancer caused by human papillomavirus Liver cancer caused by hepatitis B & C
5 Anti-Tumor Effector Mechanisms CD4 + T cells, CD8 + CTL, and NK cells - direct cytotoxicity or ADCC (NK cells) via perforin & granzymes and/or TNF family members - cytokine release (e.g., TNF, IFNγ, GM-CSF) leading to: B cells a) lysis of tumor cells b) disruption of angiogenesis c) recruitment and activation of DC, macrophages, & granulocytes - production of tumor-specific antibodies leading to: a) complement-mediated killing b) ADCC c) antibody-mediated apoptosis by disrupting oncogenic signals Macrophages - killing via ADDC - killing via production of cytokines such as TNF - killing via production of toxic oxygen or nitrogen intermediates
6 Immunotherapy Strategies Cytokine infusions (e.g. IFNa, IL-2) Induction of inflammation (e.g. CpG) Innate System Tumor-targeted antibodies (e.g.,herceptin) Adoptive transfer of tumor-specific T cells Donor lymphocyte infusions after BMT/HSCT (allogeneic bone marrow or hematopoietic stem cell transplant) Vaccination Active Adaptive System Passive Adaptive System
7 Immune Surveillance - Revival Nature 410:1107, 2001
8
9 Spontaneous tumors in wild-type and immunodeficient mice
10 T cells control latent tumors Koebel et al. Nature;450:903, 2007
11 Tumors arising in immunodeficient mice are more immunogeneic that tumors arising in wild-type mice Assayed by transplanting tumors into wildtype or immunodeficient mice
12 Tumor Elimination - Equilibrium - Escape Schreiber et al. Immunity 2004
13 Zhang et al. NEJM 348:203, 2003 Tumor-infiltrating lymphocytes correlation with survival in ovarian cancer patients
14
15 Melan-A/MART-1-specific CD8 + T cells in lymph nodes of melanoma patients Romero et al. J. Exp. Med., Volume 188(9),
16 Tumor Antigens Tumor-specific antigens Expressed by tumors ONLY Tumor-associated antigens Preferentially expressed by tumors Oncofetal antigen Expressed by tumors in adult, but also expressed by fetal (not adult) tissues
17 Types of Tumor Antigens Recognized by T cells
18 Neo-epitopes
19
20 Cancer Research 68:889, 2008
21 Use of Human Tumor Ag-Specific Cloned CTL for Identification of Tumor Antigens
22 TNFa Production
23 Serological identification of tumor antigens - Serex Some cancer patients have antibodies reactive with their own tumor Use patients sera to expression clone the tumor antigens Surprizingly, many of the antisera recognized the same tumor-associated antigens that detected by CTL
24 Passive Immunotherapy Anti-tumor monoclonal antibodies (a billion dollar business)
25 Antibody-dependent cellular cytotoxicity
26 Rituxan Pivotal Trial: Treatment of Patients With Relapsed B Lymphoma Rituxan 375 mg/m 2 (IV) Weeks Monitoring every 3 months x2 years E valuable P atients 166 Overall Res pon s e 80 (48% ) Comp lete R es pon s e 10 (6% ) P artial Re s po ns e 70 (42% ) McLaughlin et al. J Clin Oncol. (1998) 16:2825
27 CD16 (FcγRIII) mediates Herceptin and Rituxan mediate human tumor elimination in nude mice
28
29 Active Immunotherapy Vaccination
30 First vaccine to prevent human cancer! vaccine for papilloma virus for cervical cancer!
31 Successful Active Vaccination against Virus-induced Cancers Vaccine to feline leukemia virus for cats Vaccine to herpes virus (Marek s virus) in chickens Vaccine to hepatitis B in humans to prevent liver carcinoma Vaccination to HPV prevents cervical cancer
32 Active Immunization - Tumor cells or antigens Tumor cells or extracts (Melacin) Tumor peptide + adjuvant vaccine Tumor peptide loaded on dendritic cell Tumor antigen cdna vaccination Tumor antigen in recombinant virus Feeding dendritic cells dead tumors Feeding dendritic cells tumor RNA
33 Provenge load autologous DC with prostatic acid phosphatase inject into prostate cancer patient
34 Mechanisms of Tumor Escape from Immune Responses Loss of MHC or TAP Loss of co-stimulatory molecules Antigenic variation Secretion of immunosuppressive factors E.g. TGF-β, IL-10 T cells don t penetrate solid tumors Exhaustion of T cells T regulatory cells suppress anti-tumor responses
35 Cancer immunotherapy in the clinic Lawrence Fong Professor of Medicine
36 Immune recogni1on of cancer (Chen and Mellman, Immunity 2013)
37 Candidate targets for immunotherapy TNF-α IFN-α IFN-γ TGF-β (Chen and Mellman, Immunity 2013)
38 Co-s1mula1on and co-inhibi1on Antigen-presenting cell PDL1 or PDL2 T cell? + PDL1 or PDL2 PD1 CD80 or CD86 CD28 + CD80 or CD86 CTLA4 B7RP1 ICOS + B7-H3? B7-H4? HVEM MHC class I or II CD137L Peptide BTLA KIR TCR LAG3 CD137 Signal 1 + OX40L OX40 + CD70 CD CD40 CD40L GAL9 Adenosine TIM3 A2aR (Pardoll. NRC 2012) Cytokines (TGFβ, IL-1, IL-6, IL-10, IL-12, IL-18)
39 An--CTLA-4 in metasta-c Patients with metastatic melanoma Ipilimumab vs. vaccine/ipilimumab vs. vaccine OS: 10 vs vs. 6.4 months FDA approved 3/2011 melanoma (Hodi et al, NEJM 2010)
40 B Target-Lesion Change in Dacarbazine Group 100 zine group who had a response, 14 did not hav rable response. The dashed line in Panel C indi the median duration of response. An--PD-1 in metasta-c 0 A Overall Survival Patients Surviving (%) No. at Risk Nivolumab Dacarbazine Nivolumab Dacarbazine 50/210 96/208 melanoma 75 Hazard ratio for death, 0.42 (99.79% CI, ) P<0.001 Patients Who Died Median Survival no./total no. mo (95% CI) Not reached 10.8 ( ) Dacarbazine A Target-Lesion Change in Nivolumab Group 100 Maximum Change from Baseline (%) Months Nivolumab Maximum Change from Baseline (%) B Target-Lesion Change in Dacarbazine Group Maximum Change from Baseline (%) C Duration of Response 100 Patients with Complete or Partial Response (%) No. at Risk Nivolumab Dacarbazine n engl j med 372;4 nejm.org january 22, The New England Journal of Medicine Downloaded 50 from nejm.org at SAN FRANCISCO (UCSF) on January 20, For personal use only. No other uses without pe Copyright 2015 Massachusetts Medical Society. All rights reserved Nivolumab Dacarbazine Patients Dacarbazine Patients without a Durable Response no./total no. 12/84 14/ Months 23 1 Nivolumab Median Duration of Response mo (95% CI) Not reached 6.0 (3.0 not reached) or 4 selected adverse events that were con to be related to nivolumab treatment we quent and included diarrhea and an eleva nine aminotransferase level (each in 1 patients) (Table S4 in the Supplementary dix). The majority of selected adverse e grade 3 or 4 resolved quickly with a dela study treatment, glucocorticoid adminis or both, as recommended in the safety m ment guidelines for nivolumab (Table S Supplementary Appendix). DISCUSSION This phase 3, double-blind, randomize trolled study showed an overall survival with nivolumab, an anti PD-1 antibody. of death decreased by 58% with nivolu compared with dacarbazine, among pr untreated patients with advanced me The survival benefit was consistent acros prespecified subgroups, including patien poor prognostic factors. The 1-year survival rate associate nivolumab in this study (73%) is consiste the results in a phase 1 study 15,16,22 a significantly higher than the rate as with dacarbazine. Dacarbazine was ch the comparator because, until recently, standard first-line treatment in many c for patients who had melanoma without 100 (Robert et al. NEJM 2015) Patients 100 Patients
41 Combining an--ctla-4 and an-- PD Nivolumab plus Ipilimumab Median Change: Decrease of 68.1% Ipilimumab Median Change: Increase of 5.5% Best Change from Baseline in Target-Lesion Volume (%) * * * ** * * * * ** **** ** * * ********* *** ** * * 100 * ************ * Patient with confirmed response Patients (Postow et al. NEJM 2015) Table 2. Response to Treatment. Variable Best overall response no. (%)* Nivolumab plus Ipilimumab (N = 72) Patients with BRAF Wild-Type Tumors Ipilimumab (N = 37) Patients with BRAF V600 Mutation Positive Tumors Nivolumab plus Ipilimumab (N = 23) Complete response 16 (22) 0 5 (22) 0 Ipilimumab (N = 10) Partial response 28 (39) 4 (11) 7 (30) 1 (10) Stable disease 9 (12) 13 (35) 3 (13) 1 (10) Progressive disease 10 (14) 15 (41) 5 (22) 7 (70) Could not be determined 9 (12) 5 (14) 3 (13) 1 (10) Patients with objective response no. (% [95% CI]) 44 (61 [49 72]) 4 (11 [3 25]) 12 (52 [31 73]) 1 (10 [0 45])
42 Combining an--ctla-4 and an-- PD-1 B C During treatment First response After treatment discontinuation Ongoing response Nivolumab plus Ipilimumab Ipilimumab 100 Death or Disease Progression no. of patients/total no. Median Progression-free Survival mo (95% CI) 30/72 NR 25/ ( ) Hazard ratio, 0.40 (95% CI, ) P< Patients Nivolumab plus Ipilimumab Progression-free Survival (% of patients) Nivolumab plus ipilimumab (N=72) Ipilimumab (N=37) Durability of Response (wk) Ipilimumab No. at Risk Nivolumab plus ipilimumab Ipilimumab Months (Postow et al. NEJM 2015)
43 Adop-ve CELL THERAPY (ACT) Tumor is resected and cut into small fragments Tumor fragments are grown in mul1ple cultures containing highdose IL-2 Tumor infiltra1ng lymphocytes (TILs) are expanded for ~3 weeks Expanded TILs are assayed and pooled for reinfusion awer condi1oning lymphodeple1ng chemotherapy Rosenberg SA, et al. Nature Reviews Cancer 2008;8:
44 Chimeric an-gen receptor (CAR) T cells Specificity of a monoclonal an1body Not dependent on MHC Ac1vates T cells with Signals 1 & 2 Sample CAR gene construct (CD28) ê Effector func-on
45 Published OnlineFirst April 2, 2013; DOI: / CD- Genera1ons of CARs Making Better Chimeric Antigen Receptors First-generation CAR activation only Second-generation CAR dual signaling Third-generation CAR multiple ( 3) signaling mab scfv Spacer 0X BB 0X-40 CD28 ICOS ζ or FcRγ CD28 4-1BB TM Figure 1. generation C as CD8/CD3 middle, seco ing to direct signals; righ complex str mab, monoc T-body Lck lacking. Finally, the effec engineering and the modular nature of their structure, CARs defined. CARs typically ta are rapidly evolving and show great promise for their successlittle is known about mi ful use in a wide range of immunotherapies. CARs are as exqu (Sadelain etwhether al. Can Disc 2013) lesser sensitivity could rep CAR TARGETING against tumors expressin
46 The new england journal of medicine Original Article Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia Shannon L. Maude, M.D., Ph.D., Noelle Frey, M.D., Pamela A. Shaw, Ph.D., Richard Aplenc, M.D., Ph.D., David M. Barrett, M.D., Ph.D., Nancy J. Bunin, M.D., Anne Chew, Ph.D., Vanessa E. Gonzalez, M.B.A., Zhaohui Zheng, M.S., Simon F. Lacey, Ph.D., Yolanda D. Mahnke, Ph.D., Jan J. Melenhorst, Ph.D., Susan R. Rheingold, M.D., Angela Shen, M.D., David T. Teachey, M.D., Bruce L. Levine, Ph.D., Carl H. June, M.D., David L. Porter, M.D., and Stephan A. Grupp, M.D., Ph.D x 10^6 to 20.6 x 10^6 CTL019 clles/kg IV 27/30 (90%) children and adults with relapsed ALL achieved complete remission. All pa1ents developed a cytokine release syndrome. 73% with relapse-free B cell aplasia. (Maude, NEJM 10/2014)
47 A Probability of Event-free Survival No. of Patients Survival rate at 6 mo, 67% (95% CI, 51 88) Months since Infusion A Detection of CTL019+ Cells in Peripheral Blood Patient No Months C Levels of CTL019 DNA in Peripheral Blood 100,000 Positive Negative First confirmed negative Relapse B Time to First Negative Test Probability of Persistence Months since Infusion No. of Patients B Probability of Overall Survival Survival rate at 6 mo, 78% (95% CI, 65 95) Copies/µg of Genomic DNA 10,000 1, No. of Patients Months since Infusion Months since Infusion (Maude, NEJM 10/2014)
48 Cytokine Release Syndrome Fever Hypotension requiring vasopressors Hypoxemia requiring mechanical ven1la1on A Level of Interleukin-6 Interleukin-6 (pg/ml) 100,000 10,000 1, P< No Yes Severe Cytokine-Release Syndrome B Baseline Disease Burden Percent of Blast Cells in Bone Marrow P= No Yes Severe Cytokine-Release Syndrome B Baseline Disease Burden (Maude, NEJM 10/2014)
49 Discussion Groups 1. What is the best cell or cells for CAR therapy? CD8 + T cells, CD4 + T cells, γδ T cells, NK cells? Macrophages? 2. How would you make an off-the-shelf CAR T cell population that could be introduced into allogeneic recipients? 3. In addition to introducing a CAR into T cells, how else might you genetically modify the recipient cells to make them more effective or more safe?
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