CANCER IMMUNOTHERAPY · 2015-05-13 · Purposes of cancer immunotherapy 1.- Direct targeting of...
Transcript of CANCER IMMUNOTHERAPY · 2015-05-13 · Purposes of cancer immunotherapy 1.- Direct targeting of...
CANCER
IMMUNOTHERAPY
Cancer Research Center, Dpt. of Medicine & Service of Cytometry University of Salamanca. IBSAL
FARMAFORUM 2015 FACULTAD FARMACIA
The immune response to tumors
Oncogenic event
Ag uptake
Ag presentation
Lymphocyte activation
Oncogenic event
Macrophages T
B
Cytokines
T
TT
B
T
T
The immune response to tumors
CANCER IMMUNOSURVEILLANCE
Ehrlich 1909
Burnet and Thomas 1957
The immune response to tumors
- 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
Various clinical observations support the concept that theimmune system can prevent or inhibit certain cancers
Visser, Cancer Immunol Immunother 2008
Tumor antigens are recognizedby immune cells
Cancer cells harbor unique mutations that theoretically create corresponding unique tumor-specific antigens
Tumor developmentis almost always associated with recruitment and
activation of adaptive and innate immune cells
- Tumor-specific antigens (TSA)
- Tumor-associated antigens (TAA)
Cheever et al, Clin Cancer Research 2009
Goel & Sun, Chin J Cancer 2014
Schumacher & Schreiber, Science 2015
Inflammatory
cytokines
Anti-tumor primary T-cell response
Naïve CD4+
T cell
Th2 Th1
CD40/CD86
CD40LHLA II
peptideTCR
Cytotoxic
CD8+ T cell
TCR
Tumor cell
HLA-I - TAA
IL6R
IL6
APCCD40 CD86
CD154/CD28
Th1 cytokines
Inflammatory
cytokines
Pérez-Andrés, Almeida et al, Cancer 2006
Martín-Ayuso, Almeida et al, The Oncologist 2008
Inflammatory
cytokines
Anti-tumor primary T-cell response
Naïve CD4+
T cell
Th2 Th1
CD40/CD86
CD40LHLA II
PeptideTCR
Cytotoxic
CD8+ T cell
TCR
Tumor cellIL6R
APCIL6R
Inflammatory
cytokines
sb2m
sHLA-Ia
Pérez-Andrés, Almeida et al, Cancer 2006
Martín-Ayuso, Almeida et al, The Oncologist 2008
Cancer immunoevasion
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)
Regulatory cells
Defective antigen presentation
Immune suppressive mediators
Tolerance and immune deviation
Apoptosis
Mechanisms of evasion of immune attack
Tumor-derived TregsMDSCs
M2 macrophages
Cancer treatment: new strategies
Vinay et al, Sem Cancer Biol 2015 (in press)
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
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
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
Cancer treatment: new strategies
Purposes of cancer immunotherapy
1.- Direct targeting of surface tumor antigens
Rini, Sem. Oncol. 2014Bachireddy et al, Nature Rev Cancer 2015
2.- Boosting immune effector number and function
3.- Activating tumor antigen-specific immunity
4 .- Overcoming inhibitory immune supression
Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells
Purposes of cancer immunotherapy
1.- Direct targeting of surface tumor antigens
Rini, Sem. Oncol. 2014Bachireddy et al, Nature Rev Cancer 2015
2.- Boosting immune effector number and function
3.- Activating tumor antigen-specific immunity
4 .- Overcoming inhibitory immune supression
Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells
Direct targeting of surface tumor antigens
Rini, Sem. Oncol. 2014Bachireddy et al, Nature Rev Cancer 2015
1.1- Monoclonal antibodies
Humanized murine Mab: mechanisms:
ADCC
Ab-dependent phagocytosis
C’ dependent cytotoxicity
Direct cytotoxicityDC-mediate enhancement of Ag presentation
ActivatedNK cell
Direct targeting of surface tumor antigens
Weiner et al, Lancet 2009Rini, Sem. Oncol. 2014
Bachireddy et al, Nature Rev Cancer 2015
1.1- Monoclonal antibodies
CD20 (rituximab, ofatumumab, obinutuzumab) CLL, B-NHL
CD52 (alemtuzumab –Campath-) CLL, T-CLPD
CD30 (TNFRSF8) HL, ALCL
CD38 (daratumumab) MM
CD33 (gemtuzumab) AML
Anti-HER2 (Trastuzumab) Breast cancer
Anti- EGF receptor (Cefuximab) Colorectal cancer
Anti-Vascular endotelial growth factor Colorectal, breast, lung
Direct targeting of surface tumor antigens
1.2- Bispecific T-cell engagers (BiTEs)
.- BitEs may oevercome the limitations of an immunosupressivetumor environment by directly linking CTL
.- Dual specificity to a tumor antigen and to the CD3 T-cellsignalling 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 2015Kontermann & Brinkmann, Drug Dicovery Today 2015
Purposes of cancer immunotherapy
1.- Direct targeting of surface tumor antigens
Rini, Sem. Oncol. 2014Bachireddy et al, Nature Rev Cancer 2015
2.- Boosting immune effector number and function
3.- Activating tumor antigen-specific immunity
4 .- Overcoming inhibitory immune supression
Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells
Boosting immune effector number and function
2.1- Agonistic stimulation of immune effector function
Direct stimulation of immune effector function to promote tumor killing remainsan attractive option:
“TURNING ON“ THE STIMULATORS: Agonistic antibodies to CD40, CD134 (OX-40) , CD137 (4-1BB) and GITR
Riether et al, Swiss Med Wkly, 2013
Boosting immune effector number and function
2.1- Agonistic stimulation of immune effector function
Direct stimulation of immune effector function to promote tumor killing remainsan attractive option:
“TURNING ON“ THE STIMULATORS: Agonistic antibodies to CD40, CD134 (OX-40) , CD137 (4-1BB) and GITR :
Gao et al, Treds Immunol 2013,Bachireddy et al, Nature Rev Cancer 2015
NK cell-mediated ADCC Direct tumor cytotoxicity
Macrophage activationTumor-specific T-cell priming and activation
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 signallingdomains derived from the TCR and co-stimulatory molecules (CD28,
CD137 and others)
Gao et al, Trends Immunol 2013
Boosting immune effector number and function
Phase I-II clinical trials:
CART-antiCD19 relapsed/refractory CLL, B-NHL, B-ALL
CART-antiHER2/neu breast and prostate cáncer
CART-antiPSMA prostate cáncer
CART-antiCAIX renal cell carcinoma
CART-antiLewis Y lung and ovarian tumors
CART-antiCEA colon cancer
CART-antiGD2 neuroblastoma
Curran, J Gene Med 2012Brentjens et al, 2012
Grupp et al 2013
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 signallingdomains derived from the TCR and co-stimulatory molecules (CD28,
CD137 and others)
Infusion of autologous/allogeic T cells, genetically ingeneered to express chimeric antigen receptors (CARs)
Purposes of cancer immunotherapy
1.- Direct targeting of surface tumor antigens
Rini, Sem. Oncol. 2014Bachireddy et al, Nature Rev Cancer 2015
2.- Boosting immune effector number and function
3.- Activating tumor antigen-specific immunity
4 .- Overcoming inhibitory immune supression
Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells
Activating tumor antigen specific-immunity
3.2- Tumor vaccination: DC-based vaccines
Activating tumor antigen specific-immunity
3.2- Tumor vaccination: DC-based vaccines
CYTOKINES
-Vaccination:
Tumors
Infections
-Induction of tolerance:
Autoimmunity
Transplantation
Allergy
Immunotherapy
Th1
Th2
Tolerance
Th17Source: Cytokine & Growth Factor Reviews 2007; 18:5-17
(DOI:10.1016/j.cytogfr.2007.01.002)
Copyright © 2007 Elsevier Ltd
Due to their great regulatory capacities and outstanding ability to activate antigen-specific T cells, DCs have become an attractive target
in several immunotherapeutic approaches
Gao et al, Trends Immunol 2013
Activating tumor antigen specific-immunity
3.2- Tumor vaccination: DC-based vaccines
Randomized clinical trials:
.- Metastatic prostate cancer
.- B-cell lymphomas
.- Metastatic melanoma:
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
Autologous idiotype protein conjugated to keyhole limpet hemocyanin(KLH)
Vaccination with gp100 peptide alone, with or without high dose of IL2
Which is the optimal DC status to induce a specific T-cell polarization?
Immune response Tolerance
Additional challenges: •Antigen dose• Number of cells• Requirements for repetitive doses• Route of administration, etc.
Bakdash et al, Front Immunol 2013Chung et al, Clinical and Developmental Immunology 2013
A first challenge is the identification ofa maturation-resistant subtype of DC
Immunotherapy-relevant DC subsets
Wimmers et al, Frontiers in Immunology 2014
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
Purposes of cancer immunotherapy
1.- Direct targeting of surface tumor antigens
Rini, Sem. Oncol. 2014Bachireddy et al, Nature Rev Cancer 2015
2.- Boosting immune effector number and function
3.- Activating tumor antigen-specific immunity
4 .- Overcoming inhibitory immune supression
Cancer immunotherapy relies on the principle of mobilizing the host immune system to fight against cancer cells
Riether et al, Swiss Med Wkly, 2013
Overcoming inhibitory immune supression
4.1- Co-inhibitory molecules
Immune effector activity is finely tuned by activating and inhibitory signals known as immune checkpoints:
Rini, Sem Oncol 2014Bachireddy et al, Nature Rev Cancer 2015
Rowdo et al, Front Immunol 2015
Overcoming inhibitory immune supression
4.1- Co-inhibitory molecules
Major targeted co-inhibitory molecules:
Immune effector activity is finely tuned by activating and inhibitory signals known as immune checkpoints:
Rini, Sem Oncol 2014Bachireddy et al, Nature Rev Cancer 2015
Rowdo et al, Front Immunol 2015
“TURNING OFF” THE BRAKES:
antibodies against CTLA-4
(CD152), PD-1 (CD279) and PD-L1
Treg Treg
DCDC
CTL
CTLTumorcell
CTLA-4
PD-1
PD-1L
Overcoming inhibitory immune supression
4.1- Co-inhibitory molecules
Major targeted co-inhibitory molecules:
KIRs: .- Lirilumab: AML
CTLA-4 & PD1 combined therapy:.- Metastatic melanoma (I)
Immune effector activity is finely tuned by activating and inhibitory signals known as immune checkpoints:
CTLA-4 (CTL-associated antigen 4, CD152):.- Ipilimumab: metastatic melanoma, B-NHL
“TURNING OFF” THE BRAKES:
antibodies against CTLA-4
(CD152), PD-1 (CD279) and PD-L1
PD1-PD1 ligand 1:.- Pidilizumab: relapse or refractory DLBCL.- Nivolumab: relapsed or refractory HL, B/T-NHL
& refractory melanoma
Rini, Sem Oncol 2014Bachireddy et al, Nature Rev Cancer 2015
Rowdo et al, Front Immunol 2015
However, despite the best efforts, only limited success has been achieved in developing effective antitumor immunotherapies
CANCER IMMUNOTHERAPY: CONCLUDING REMARKS
With the identification of new immune-based targets, cancer immunotherapy is now beginning to resurface as a promising treatment strategy
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
Integrating an optimized vaccine preparation with a local immune activation seems to be the future of treatment platforms
Pizzurro & Barrio, Front Immunol 2015