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


CANCER IMMUNOSURVEILLANCE

Ehrlich 1909

Burnet and Thomas 1957


- 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


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


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


1.1- Monoclonal antibodies

Humanized murine Mab: mechanisms:

ADCC

Ab-dependent phagocytosis

C’ dependent cytotoxicity

Direct cytotoxicityDC-mediate enhancement of Ag presentation

ActivatedNK cell


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


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

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


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


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


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)

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

http://www.cgfr.co.uk/article/S1359-6101(07)00003-2/abstract



Gao et al, Trends Immunol 2013



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

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



Major targeted co-inhibitory molecules:




“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



Major targeted co-inhibitory molecules:

KIRs: .- Lirilumab: AML

CTLA-4 & PD1 combined therapy:.- Metastatic melanoma (I)


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



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

cancer immunotherapy · 2015-05-13 · purposes of cancer immunotherapy 1.- direct targeting of...

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