Imm 532 2/25/16 Tumor Immunology Phil Greenberg
Tumor Immunology Study of the interactions between the immune system and cancer - antigenic properties of tumor cells - host immune response to tumor cells - immunologic impact of growing tumor on host - impact of immune response on tumor Because most antigens initially expressed by tumors are self-proteins, tumors challenge the fine balance between maintenance of self-tolerance and immune activation Autoimmunity Tumorimmunity Transgenic and knock-out mice are providing better models of human malignancy and new insights into the natural interactions between the immune system and tumors, and are fostering development and testing of new immunotherapeutic strategies
Cancer Immunosurveillance Hypothesis the immune system recognizes and eliminates developing tumors Paul Ehrlich, 1909 the primary function of cellular immunity is not to promote allograft rejection but rather to protect from neoplastic disease, thereby maintaining tissue homeostasis in complex multicellular organisms. Lewis Thomas, 1957 It is by no means inconceivable that small accumulations of tumour cells may develop and because of their possession of new antigenic potentialities provoke an effective immunological reaction with regression of the tumour and no clinical hint of its existence. Sir Macfarlane Burnet 1957 inheritable genetic changes must be common in somatic cells and a proportion will represent a step toward malignancy. It is an evolutionary necessity that there should be some mechanism for eliminating such dangerous mutant cells and it is postulated this mechanism is of immunological character. Sir Macfarlane Burnet, 1964
For the hypothesis: Trouble ahead,trouble behind Fundamental Prediction: Immunodeficient individuals should display a dramatic increase in tumor incidence BUT: Ahead: Prospective monitoring of patients rendered immunocompromised found only uncommon cancers such as lymphoblastic lymphomas and Kaposi s sarcoma with increased frequency -as more was learned about microbial etiologies of malignancies, it became clear that most cancers in immuno-deficient individuals were virus-associated, suggesting surveillance of pathogens Behind: Retrospective epidemiologic studies reviewing disease incidence in patients with heritable immuno-deficiencies revealed a very limited pattern of increased cancer risk -the common epithelial cancers seen in adulthood (such as colon, lung, breast, prostate cancer, etc.), with the exception of gastric cancer (from H. pylori), were not increased in this population
Then, Big Trouble for the Immunosurveillance Hypothesis: An Experiment! No evidence in immunodeficient mice Tumor development after 3-methylcholanthrene in immunologically deficient athymic-nude mice. Stutman,Osias Science 183:534 (1974) Abstract- Athymic-nude (nu/nu) mice and normal (nu/+) mice showed no differences in either latent period or incidence of local sarcomas or lung adenomas within 120 days after administration of 3-methylcholanthrene at birth. However, nu/nu mice were incapable of rejecting allogeneic skin grafts for the duration of the experiment. These results argue against an active role of thymus-dependent immunity as surveillance mechanism preventing tumor development.
For the True Believers : What could be wrong with this data set? A potential caveat to the interpretation of cancer incidence data in heritable immunodeficiency patients is that individuals with more severe immunodeficiency tend not to live past their thirties or forties. Thus, a more subtle effect of immunodeficiency not associated with pathogens on the incidence of cancers, which generally appear later in life, would not be observable. Nude mice have atrophic thymi and don t lack T cells but rather have severely reduced numbers of T cells and poor T cell dependent immune responses. Thus, nude mice are capable of some degree of T cell dependent immunity, and have fully intact (? hyperactive) innate immune responses. The strain of nude mice used in the studies, CBA/H, have the highly active isoform of aryl hydoxylase that converts MCA to its carcinogenic metabolite, making the mice highly susceptible to such carcinogenesis The use of newborn mice in these studies underestimates contributions from a mature immune system
27 years later Immune Surveillance Revisited ala Bob Schreiber Increased Incidence of MCA-Induced Tumors Detected In Mice With Well- Defined Genetic Immunodeficiencies SHANKARAN et al. Nature 410:1107 (2001) SubQ MCA Injection 80-160 days Lack T and B cells Lack IFNγR or signaling capacity Wild Type (normal mice)
Examined development of spontaneous tumors in normal and immunodeficient mice
Examined if tumors that developed in immunodeficient mice were actually immunogenic and would have been rejected by normal mice With improved methods for targeted ablation of distinct components of an immune response and sensitive assays for tumor resistance, virtually all of the individual cells and factors that contribute to innate and adaptive immunity have been shown to impact tumor outgrowth
The DNA-Damage Response: Getting Tumor Elimination/Surveillance Going S Gasser et al, Nature, 436:1186 (2005)
Innate and adaptive immune surveillance responses to a developing tumor
RD Schreiber et al; Science 2011
Strategy To Directly Test For Equilibrium Phase 25 µg MCA Control mab 200 Days Divide non-tumor bearing Wt or RAG2 -/- mice into 2 groups No mice developed any tumors Wt 129/Sv Mice or RAG2 -/- Mice α-ifnγ α-cd4/cd8 Remove tumor bearing mice from group Koebel et al. Nature 450:903 (2007) 40% of Wt and 0% of RAG2 -/- developed tumors
A re-analysis of the state(s) of tumor dormancy Immune Dormancy is an active and dynamic state
Is there evidence for such naturally occurring T cell responses mediating surveillance and/or editing of spontaneous human tumors?
Tumor Infiltrating Lymphocytes- Why are they (sometimes) there? Do they influence tumor progression and survival? Stage III or IV ovarian CA. Complete, partial, or no response to rx Zhang et al. N Engl J Med 2003;348:203-213
Tumor Infiltrating Lymphocytes- Colon Cancer Immuno-staining and cdna analysis of Colon Ca biopsies Clinical outcomes stratified based on frequency of primed/memory T cells in initial biopsy F Pages et al, NEJM, 353:2654 (2005)
International Working Group: Correlating The Immune Contexture of Tumors with Outcome
Meta-analysis of impact of T cell infiltrates in 20 cancer types Fridman et al, Nat Rev Cancer, 2012
CD8+ CTL: The critical effector cell for tumor elimination
Where do tumor antigens recognized by T cells come from?
Human tumor-associated antigens: Likelihood of antigen retention in tumor cells with pressure by a T cell response Cancer-testes antigens
Tumor Evasion/Escape Mechanisms If human tumors express antigens that can be recognized by T cells and B cells, why do so many people develop progressive tumors? General explanations for evasion: a) BIOLOGY: Most tumor cells are not suficiently different from normal cells, and may be ignored and regarded by the immune system as self b) DEVELOPMENT: Prevention of autoimmunity (recognition of self) had priority over tumor surveillance c) EVOLUTION: Efficient surveillance for tumors, which mostly occur long after puberty, not likely to have been selected for during evolution Possible mechanisms of escape if tumor is recognized : 1) Antigen loss 2) MHC down-regulation 3) Anergy 4) Production of immunosuppressive factors 5) Physical exclusion of lymphocytes by abnormal tumor vasculature 6) Induction of regulatory T cells and/or myeloid derived suppressor cells 7) Exhaustion: Induced dysfunction/hypofunction in responding T cells
Immunotherapy Strategies 1) Cytokine infusions 2) Induction of local inflammation 3) Activation of macrophages (αcd40 Ab) or NK cells (KIR mismatching) 4) Vaccination 5) Immunomodulatory Abs: -Checkpoint blockade -Costimulation -deplete suppressive cells Active Adaptive System 6) Tumor-targeted antibodies (e.g.herceptin) 7) Adoptive transfer of tumor-specific T cells -engineer an immune response 8) Allogeneic BMT/HSCT (bone marrow or hematopoietic stem cell transplant) + donor lymphocyte infusions, T cells, or NK cells Innate System Passive Adaptive System
Cancer Immunotherapy: Taking tumor immunology into prime time Highlighted in special issues 2013-2014:
Vaccination Strategies to enhance vaccine activity
Shrinkage of mediastinal metastasis of melanoma after vaccination 4 cm mass prior to vaccination 70% regression 4 months post-vaccine
Regression of lymphoma following idiotype-pulsed dendritic cell vaccine Pre-vaccine 11 months post-vaccine
Opportunities for Preventive Vaccines: ~20% of human cancers attributable to infectious pathogens Bacterium: H. pylori Stomach cancer Virus: HPV Preventive Vaccines Virus: HBV Cervical cancer Liver cancer Virus: HCV Virus: EBV Virus: HHV8 Liver cancer NPC (NPC = Naso-Pharyngeal Ca.) KS (KS = Kaposi s Sarcoma) Main cancer caused by agent Other cancer(s) caused by agent Other agents 0 100,000 200,000 300,000 400,000 500,000 600,000 Annual number of cases Adapted from Parkin, Int J Cancer 118:3030, 2006
Tumor-Targeted Antibodies or drug Mφ (Kill by direct lysis or apoptosis)
IMMUNE MODULATION: Blocking Inhibitory Signals or Providing Co-stimulatory Signals to T cells to Improve The Generation and Activity of Effector T Cells Block Inhibition: checkpoint blockade Anti-CTLA-4: mab approved Anti-PD-1: mab approved Enhance Stimulation Anti-CD137: Phase II Anti-OX40: Phase I
Combining CTLA-4 Blockade With Vaccination Can Promote Therapeutic T cell Responses To Established Tumors Treatment of B16 Melanoma in mice with combined B16/GM-CSF vaccine and CTLA-4 Blockade αctla-4 mab +B16/GM-CSF vaccine αctla-4 mab alone Control mab +B16/GM-CSF vaccine Control mab Days But responses not necessarily entirely tumor-specific Van Elsas et al. JEM, 1999
CTLA-4 Blockade In Humans: Antitumor immunity, Autoimmunity The good news. The bad news. Skin Colon Colon CD3 Liver Phan et al. PNAS (2003) 100:8372
PD-1 blockade in humans with mab: Regression of advanced tumors Topalian, et al, NEJM (2012)
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Responses to checkpoint blockade have been dramatic and unprecedented: Who can be expected to respond? In patients responding to checkpoint blockade, responses appear to be primarily to neoantigens formed by mutations A value of 10 mutations per Mb of coding DNA yields ~150 nonsynonomous mutations in expressed genes
Nature of Anti-tumor Responses Elicited by Checkpoint Inhibitors Responses appear to largely reflect recognition of novel epitopes derived from neoantigens created by mutations in cellular genes (Gubin et al; Nature, (2014) 515:577-81) Consequently, therapeutic benefit most often detected in tumors with highest mutational load, such as melanomas and lung cancers (Snyder et al; N Engl J Med, 2014) CTLA-4 blockade tends to provide benefit by broadening host T cell responses to tumor- promotes priming of new responses (Kvistborg et al; Sci Transl Med, 2014) PD-1 blockade tends to provide benefit by rescuing function of T cells already in the tumor that have been rendered dysfunctional via chronic signaling through PD-1 (Tumeh et al; Nature, (2014) 515: 568-71)
Adoptive Transfer of Tumor-Specific T Cells Large-scale expansion Select tumorreactive T cell clones or polyclonal T cells Expand Intravenous Infusion Stimulate with antigen or genetically modify T cells from blood or tumor infiltrate Administer IL2 Lymphodeplete
Adoptive T Cell Transfer Can Be Used To Achieve Very High Frequencies Of Tumor-Reactive CD8+ T cells in vivo Transient lymphodepletion can provide a milieu very favorable to the in vivo expansion, survival, and persistence of transferred tumor-reactive T cells Melanoma Patient #1 Melanoma Patient #2 Dudley, et al, Science (2002) 298:850
Obstacles To Efficacy Of Adoptive T cell Therapy Addressable With Genetic Modification Specificity Survival Localization Effector Function
Transfer of T cells modified to express a chimeric receptor targeting CD19 has achieved unprecedented success in the therapy of B cell malignancies CAR T cells Maude SL, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med;;371:1507-17 (2014) Davila ML et al. Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia. Sci Transl Med; 6:224ra25 (2014) Brentjens RJ et al. CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Sci Transl Med; 5:177ra38 (2013) Kochendorfer JN et al. Donor-derived CD19- targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood; 122:4129 (2013)
T Cell Engineering: Receptors and more
Cancer Immunotherapy: Taking tumor immunology into prime time Highlighted in special issues 2015:
Cancer Immunology: Living in the bright lights And now, a series of dedicated journals: Editors: Phil Greenberg Robert Schreiber
Will Immunotherapy be the 4 th pillar of cancer therapy in the next decade? Surgery Radiation Therapy Chemo- Therapy Immuno- Therapy
Summary Basic discoveries concerning the normal function and regulation of host immunity and biologic basis for malignancy have provided many targets and strategies for cancer immuno-therapy. The availability of reagents for manipulating discrete pathways that qualitatively and quantitatively influence immune responses and the ability to provide potent immune responses to selected tumor antigens have brought tumor immunology to the forefront of molecular medicine and cancer therapy. The challenges remain to both elucidate further insights into the immunobiology of the tumor-host relationship, and to apply the advances from basic studies in immunology to the design of effective strategies to treat human malignancy