CANCER IMMUNOTHERAPY. Cancer Research Center, Dpt. of Medicine & Service of Cytometry University of Salamanca. IBSAL

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1 FARMAFORUM 2015 FACULTAD FARMACIA CANCER IMMUNOTHERAPY Cancer Research Center, Dpt. of Medicine & Service of Cytometry University of Salamanca. IBSAL

2 The immune response to tumors Oncogenic event

3 The immune response to tumors Oncogenic event Ag uptake CANCER IMMUNOSURVEILLANCE Ehrlich 1909 Burnet and Thomas 1957 B T T T Macrophages B Ag presentation Lymphocyte activation T T T Cytokines

4 The immune response to tumors Various clinical observations support the concept that the immune system can prevent or inhibit certain cancers - Tumors without clinical evidence found in autopsies - Inflammatory response and lymphoid infiltrates in tumors (TIL) - Some tumors show spontaneous regresions - Higher incidence of tumors in immunocompromised patients - Higher incidence of tumors in children and elderly subjects Visser, Cancer Immunol Immunother 2008

5 Tumor antigens are recognized by immune cells - Tumor-specific antigens (TSA) Cancer cells harbor unique mutations that theoretically create corresponding unique tumor-specific antigens - Tumor-associated antigens (TAA) Cheever et al, Clin Cancer Research 2009 Goel & Sun, Chin J Cancer 2014 Schumacher & Schreiber, Science 2015 Tumor development is almost always associated with recruitment and activation of adaptive and innate immune cells

6 Anti-tumor primary T-cell response Inflammatory cytokines IL6 IL6R Tumor cell APC CD40 CD86 CD154/CD28 TCR HLA-I - TAA HLA II peptide TCR CD40/CD86 CD40L Cytotoxic CD8+ T cell Naïve CD4+ T cell Th1 cytokines Inflammatory cytokines Th 2 Th 1 Pérez-Andrés, Almeida et al, Cancer 2006 Martín-Ayuso, Almeida et al, The Oncologist 2008

7 Anti-tumor primary T-cell response Inflammatory cytokines IL6R Tumor cell APC TCR IL6R HLA II Peptide Inflammatory cytokines TCR CD40/CD86 CD40L Naïve CD4+ T cell Cytotoxic CD8+ T cell sb2m shla-ia Th 2 Th 1 Pérez-Andrés, Almeida et al, Cancer 2006 Martín-Ayuso, Almeida et al, The Oncologist 2008

8 Cancer immunoevasion Mechanisms of evasion of immune attack Regulatory cells Tumor-derived Tregs MDSCs M2 macrophages Defective antigen presentation Immune suppressive mediators Tolerance and immune deviation Apoptosis Selection of tumor variants resistant to immune effectors and progressive formation of an immune suppressive environment within the tumor ( immunoediting ) Joyce & Fearon, Science 2015 Vinay et al, Sem Cancer Biol 2015 (in press)

9 Cancer treatment: new strategies For efficient eradication of well-established tumors: combinatorial approaches not only targeting cancer cells, but also target tumor supportive microenviroment and activate anti-tumor adaptive immunity Vinay et al, Sem Cancer Biol 2015 (in press)

10 Cancer treatment: new strategies Advances in our understanding of the mechanisms of immune regulation and the complex interactions between tumor cells and the immune system have provided solid basis for the development of:.- Combinatorial approaches.- Novel immunotherapy strategies

11 Cancer treatment: new strategies Advances in our understanding of the mechanisms of immune regulation and the complex interactions between tumor cells and the immune system have provided solid basis for the development of:.- Combinatorial approaches.- Novel immunotherapy strategies An increasing number of clinical trials are currently underway to stimulate the immune system to combat cancer

12 Purposes of cancer immunotherapy Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells 1.- Direct targeting of surface tumor antigens 2.- Boosting immune effector number and function 3.- Activating tumor antigen-specific immunity 4.- Overcoming inhibitory immune supression Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

13 Purposes of cancer immunotherapy Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells 1.- Direct targeting of surface tumor antigens 2.- Boosting immune effector number and function 3.- Activating tumor antigen-specific immunity 4.- Overcoming inhibitory immune supression Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

14 Direct targeting of surface tumor antigens 1.1- Monoclonal antibodies Humanized murine Mab: mechanisms: ADCC Activated NK cell Ab-dependent phagocytosis C dependent cytotoxicity Direct cytotoxicity DC-mediate enhancement of Ag presentation Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

15 Direct targeting of surface tumor antigens 1.1- Monoclonal antibodies CD20 (rituximab, ofatumumab, obinutuzumab) CD52 (alemtuzumab Campath-) CD30 (TNFRSF8) CD38 (daratumumab) CD33 (gemtuzumab) CLL, B-NHL CLL, T-CLPD HL, ALCL MM AML Anti-HER2 (Trastuzumab) Anti- EGF receptor (Cefuximab) Anti-Vascular endotelial growth factor Breast cancer Colorectal cancer Colorectal, breast, lung Weiner et al, Lancet 2009 Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

16 Direct targeting of surface tumor antigens 1.2- Bispecific T-cell engagers (BiTEs).- BitEs may oevercome the limitations of an immunosupressive tumor environment by directly linking CTL.- Dual specificity to a tumor antigen and to the CD3 T-cell signalling complex.- On-going Phase II Clinical Trials: - Blinatumomab (CD3 CD19) BCP-ALL - Bispecific CD3 CD33 AML - Bispecific CD3 CD20 B-NHL - Bispecific CD3 HER2 Breast ca. Bachireddy et al, Nature Rev Cancer 2015 Kontermann & Brinkmann, Drug Dicovery Today 2015

17 Purposes of cancer immunotherapy Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells 1.- Direct targeting of surface tumor antigens 2.- Boosting immune effector number and function 3.- Activating tumor antigen-specific immunity 4.- Overcoming inhibitory immune supression Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

18 Boosting immune effector number and function 2.1- Agonistic stimulation of immune effector function Riether et al, Swiss Med Wkly, 2013 Direct stimulation of immune effector function to promote tumor killing remains an attractive option: TURNING ON THE STIMULATORS: Agonistic antibodies to CD40, CD134 (OX-40), CD137 (4-1BB) and GITR

19 Boosting immune effector number and function 2.1- Agonistic stimulation of immune effector function Direct stimulation of immune effector function to promote tumor killing remains an attractive option: TURNING ON THE STIMULATORS: Agonistic antibodies to CD40, CD134 (OX-40), CD137 (4-1BB) and GITR : NK cell-mediated ADCC Direct tumor cytotoxicity Tumor-specific T-cell priming and activation Macrophage activation Gao et al, Treds Immunol 2013, Bachireddy et al, Nature Rev Cancer 2015

20 Boosting immune effector number and function 2.2- Chimeric antigen receptor T cells (CAR T cells) Synthetically engineered receptor composed of a single-chain Ab fragment (tumor recognition) coupled with intracelular signalling domains derived from the TCR and co-stimulatory molecules (CD28, CD137 and others) Gao et al, Trends Immunol 2013

21 Boosting immune effector number and function 2.2- Chimeric antigen receptor T cells (CAR T cells) Synthetically engineered receptor composed of a single-chain Ab fragment (tumor recognition) coupled with intracelular signalling domains derived from the TCR and co-stimulatory molecules (CD28, CD137 and others) Phase I-II clinical trials: Infusion of autologous/allogeic T cells, genetically ingeneered to express chimeric antigen receptors (CARs) CART-antiCD19 CART-antiHER2/neu CART-antiPSMA CART-antiCAIX CART-antiLewis Y CART-antiCEA CART-antiGD2 relapsed/refractory CLL, B-NHL, B-ALL breast and prostate cáncer prostate cáncer renal cell carcinoma lung and ovarian tumors colon cancer neuroblastoma Curran, J Gene Med 2012 Brentjens et al, 2012 Grupp et al 2013

22 Purposes of cancer immunotherapy Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells 1.- Direct targeting of surface tumor antigens 2.- Boosting immune effector number and function 3.- Activating tumor antigen-specific immunity 4.- Overcoming inhibitory immune supression Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

23 Activating tumor antigen specific-immunity 3.2- Tumor vaccination: DC-based vaccines

24 Activating tumor antigen specific-immunity 3.2- Tumor vaccination: DC-based vaccines Due to their great regulatory capacities and outstanding ability to activate antigenspecific T cells, DCs have become an attractive target in several immunotherapeutic approaches CYTOKINES -Vaccination: Tumors Infections Immunotherapy Source: Cytokine & Growth Factor Reviews 2007; 18:5-17 (DOI: /j.cytogfr ) Copyright 2007 Elsevier Ltd Th 1 Th 2 Th 17 Tolerance -Induction of tolerance: Autoimmunity Transplantation Allergy

25 Activating tumor antigen specific-immunity 3.2- Tumor vaccination: DC-based vaccines Randomized clinical trials:.- Metastatic prostate cancer Autologous peripheral blood mononuclear cells pulsed with a fusion protein of granulocyte macrophage colony-stimulating factor (GM-CSF) and the prostate cancer antigen prostatic acid phosphatase.- B-cell lymphomas Autologous idiotype protein conjugated to keyhole limpet hemocyanin (KLH).- Metastatic melanoma: Vaccination with gp100 peptide alone, with or without high dose of IL2 Gao et al, Trends Immunol 2013

26 Which is the optimal DC status to induce a specific T-cell polarization? Immune response Tolerance A first challenge is the identification of a maturation-resistant subtype of DC Additional challenges: Antigen dose Number of cells Requirements for repetitive doses Route of administration, etc. Bakdash et al, Front Immunol 2013 Chung et al, Clinical and Developmental Immunology 2013

27 Immunotherapy-relevant DC subsets Wimmers et al, Frontiers in Immunology 2014

28 Which is the best APC subset for immunotherapy? Conventional assays: Infusion of in vitro generated Mo-derived DCs Poor clinical results (cancer immunotherapy) On-going assays: Infusion of naturally circulating DCs.- Preliminary clinical trials showed increased survival rates (Melanoma).- Treatment paradigm: to include several primary DC subsets aiming at reaching synergistic effects between various APCs Wimmers et al, Frontiers in Immunology 2014

29 Purposes of cancer immunotherapy Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells 1.- Direct targeting of surface tumor antigens 2.- Boosting immune effector number and function 3.- Activating tumor antigen-specific immunity 4.- Overcoming inhibitory immune supression Rini, Sem. Oncol Bachireddy et al, Nature Rev Cancer 2015

30 Overcoming inhibitory immune supression 4.1- Co-inhibitory molecules Immune effector activity is finely tuned by activating and inhibitory signals known as immune checkpoints: Riether et al, Swiss Med Wkly, 2013 Rini, Sem Oncol 2014 Bachireddy et al, Nature Rev Cancer 2015 Rowdo et al, Front Immunol 2015

31 Overcoming inhibitory immune supression 4.1- Co-inhibitory molecules Immune effector activity is finely tuned by activating and inhibitory signals known as immune checkpoints: Major targeted co-inhibitory molecules: DC CTLA-4 CTL DC Treg Treg Tumor cell PD-1L PD-1 CTL TURNING OFF THE BRAKES: antibodies against CTLA-4 (CD152), PD-1 (CD279) and PD-L1 Rini, Sem Oncol 2014 Bachireddy et al, Nature Rev Cancer 2015 Rowdo et al, Front Immunol 2015

32 Overcoming inhibitory immune supression 4.1- Co-inhibitory molecules Immune effector activity is finely tuned by activating and inhibitory signals known as immune checkpoints: Major targeted co-inhibitory molecules: CTLA-4 (CTL-associated antigen 4, CD152):.- Ipilimumab: metastatic melanoma, B-NHL PD1-PD1 ligand 1:.- Pidilizumab: relapse or refractory DLBCL.- Nivolumab: relapsed or refractory HL, B/T-NHL & refractory melanoma CTLA-4 & PD1 combined therapy:.- Metastatic melanoma (I) KIRs:.- Lirilumab: AML TURNING OFF THE BRAKES: antibodies against CTLA-4 (CD152), PD-1 (CD279) and PD-L1 Rini, Sem Oncol 2014 Bachireddy et al, Nature Rev Cancer 2015 Rowdo et al, Front Immunol 2015

33 CANCER IMMUNOTHERAPY: CONCLUDING REMARKS With the identification of new immune-based targets, cancer immunotherapy is now beginning to resurface as a promising treatment strategy However, despite the best efforts, only limited success has been achieved in developing effective antitumor immunotherapies The key to the long-term success of cancer immunotherapy is to identify optimal tumor antigens/targets, develop predictive biomarkers, better understand the immune tumor environment and overcome issues with toxicity Ultimately, the most effective cancer therapies may consist of combinations of diverse immunotherapy strategies and rational combinations with standard therapies such as targeted therapies and conventional chemotherapy

34 Integrating an optimized vaccine preparation with a local immune activation seems to be the future of treatment platforms Pizzurro & Barrio, Front Immunol 2015