PASSATO E PRESENTE DELL’IMMUNOTERAPIA ANTITUMORALE

Gilberto Filaci

IMMUNOTHERAPY OF TUMORS

Aim

IMMUNOTHERAPY OF TUMORS

Aim

IMMUNOREGULATION IN TUMOR MICROENVIRONMENT

Types of Immunotherapy

Passive ActiveModulatory

• mAbs

• Adoptive celltransfer

• Cytokines

• Checkpointinhibitors

• Vaccines

Passive Immunotherapy

• mAbs

• Adoptive celltransfer

Membrane Ag directed (i.e., anti-CD20)

Cytokine directed (i.e., anti-VEGF)

Kinase inhibitor (i.e., anti-HER2)

Bispecific antibodies (i.e., bite)

LAK

TILs

CAR-T, CAR-NK

Active Immunotherapy

• Vaccines

Tumor lysate

Peptides

Purified tumor associated antigen

DC-based vaccines

Idiotype-based vaccines

Gene vaccines

Modulatory Immunotherapy

• Cytokines

• Checkpointinhibitors

Interleukin 2

IFNs

Anti-CTLA-4

Anti-PD1

Anti-PD-L1

Sakaguchi et al.,Cell 133, May 30, 2008

Treg infiltrate tumors

Blood. 2012;119(24):5688-5696

2016

CANCER IMMUNOSCORE

a) Prognosis

b) Prediction on IT efficacy (i.e., PD1 or PD-L1-3 expression)

c) Indication of the most appropriate therapy or combination protocol

Aims

1. Phenotypic/functional characterization of immune infiltrate

2. Definition of molecular patterns expressed in the tumor

Passive Immunotherapy

• mAbs

• Adoptive celltransfer

Membrane Ag directed (i.e., anti-CD20)

Cytokine directed (i.e., anti-VEGF)

Kinase inhibitor (i.e., anti-HER2)

Bispecific antibodies (i.e., bite)

LAK

TILs

CAR-T, CAR-NK

mAbs in cancer treatment

Immunological mechanisms of action Non-Immunological mechanisms of action

Radio-immunotherapy and Theranostic applications

PREDICTIVE RELEVANCE

Mechanisms of action for RIT

RIT TRIALS

CHECKPOINT INHIBITORS (MODULATORS)

CHECKPOINT INHIBITORS (MODULATORS)

ANTI-CTLA-4 mAb

CHECKPOINT INHIBITORS

Cancer Metastasis Rev. 2016 Nov 21.

Zanetti M. Nat Rev Clin Oncol. 2016 Jun 1.

Neo-antigens: NO TOLERANCE Unmutated, self antigens: TOLERANCE

HIGH AVIDITY immune response LOW AVIDITY immune response

Zanetti M. Nat Rev Clin Oncol. 2016 Jun 1.

Zanetti M. Nat Rev Clin Oncol. 2016 Jun 1.

TELOMERASE All cancers

Tumor antigens

(7) Universal tumor antigen

(Clin Cancer Res 2009;15(17):5323–37)

How to increase the response rate?

• HLA restriction: needs for widening HLA-haplotype coverage

• Needs for activation of both CD4+ and CD8+ T cells

• Needs for appropriate innate immunity activation

USE OF MULTIPLE EPITOPES

+

COMPLEMENTARY ADJUVANTS

Stage IV prostate or renal cancer

Telomerase peptides: p540-548(GX301 vaccine) p611-626

p672-686p766-780

Montanide + Imiquimod

No grade 3-4 side effectsNo reticulocyte reductionNo B or T lymphocyte reductionNo autoimmunity

OVERALL IMMUNOLOGICAL RESPONSE RATE = 100%

OS (PROSTATE CANCER PATIENTS)

Our series= 14 months

Literature = 9 months

Does the schedule of vaccination matter?

Does the schedule of vaccination matter?

Does the schedule of vaccination matter?

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AlessandriaTorino

Milano

Trento

Verona

Pordenone

Siena

Roma

Bari33 Centers

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Madrid

MED-GX301-02

25 Centers: 18 in Italy 7 in Spain

Napoli

, 2014

WHAT’S THE RIGHT STRATEGY?

Inhibitory molecules

Activatory molecules

Innate immune cells

T Lymphocytes

Treg

NK cells

Cytokines

Combinatorial therapy with:

Chemotherapy

Radiotherapy

Targeted therapy

Two Immunotherapies(i.e. vaccine + CI)

THANKS TO… your patience