The Science of immunotherapy

Rahul Ravilla MD

Genito-Urinary Oncology

New York Oncology Hematology

Albany Medical Center

Objectives

What is immunotherapy?

A brief history of

immunotherapy in cancer

Physiology of

immunotherapy

What is immunotherapy?

ASCO defines Immunotherapy, also called biologic therapy, as a type of cancer treatment

that boosts the body's natural defenses to fight cancer. It uses substances made by the body

or in a laboratory to improve or restore immune system function. Immunotherapy may work

by:

Stopping or slowing the growth of cancer cells

Stopping cancer from spreading to other parts of the body

Helping the immune system work better at destroying cancer cells

The History..

1893 1960s 1980s 2000s Now

Graft-versus-LeukemiaEffect

BCG in bladder cancerColey’s toxin Monoclonal antibodies Cellular therapies

The formidable enemy “Cancer Cell”

Cell 2011 144, 646-674DOI: (10.1016/j.cell.2011.02.013)

Tumor Mutational Burden and Response Rate to PD-1 Inhibition

Yarchoan et al. NEJM 2017

The general

“Antigen presenting cell”

Soldiers of immunotherapy “T cells”

Modified from Schalper et al 2018 ASCO-SITC symposium

T Cell

Agonist Antagonist

CTLA4

PD-1

TIM-3

BTLA

VISTA

LAG-3

CD28

OX40

GITR

CD137

CD27

HVEM

Traitors “Tumor microenvironment”

Virgilio et al. Nature ReviewsCancer volume 18, pages 601–618 (2018)

Weapons: “Monoclonal antibodies”

CTLA-4

and PDL-1

blockade

Adapted from Chen DS, et al. Molecular pathways: next-generation immunotherapy--inhibiting programmed death-ligand 1 and

programmed death-1. Clin Cancer Res. 2012;18:6580-6587 with permission from AACR.

Tumor Immunology Overview

Priming and

activation of

T-cells

Can you generate

tumor-killing T-cells?

Antigen priming

Can the T-cells

get to the tumor?

T-cell trafficking

Can the T cells

see the tumor?

Peptide-MHC

expression

Can the T-cells

be turned off?

Inhibitory cytokines

Can the T-cells

be turned off?

PD-L1 expression

on tumor cells

IFN-γ–mediated

upregulation of

tumor PD-L1

PD-L1/PD-1–mediated

inhibition of tumor

cell killing

Tumor cell

IFN-γR

IFN-γ

OtherNFκB PI3K

PD-1

PD-L1

PD-L2

T-cell receptor

MHC-1

CD28

Shp-2

B7.1

Dendritic

cell

Immunotherapy targets

Dendritic cell

TUMOR

Naïve T cell

Activated T cell

M2

Vaccines

• Therapeutic vs Prophylactic

• Monovalent vs Polyvalent

• May elicit excellent local

response “BCG in Bladder”

• Not very effective in

eliciting systemic response

• May play role in

combination

immunotherapies

Checkpoint inhibitors

PD-1 inhibitors (Bind on T cell)

Nivolumab (Opdivo)

Pembrolizumab (Keytruda)

PD-L1 inhibitors (Bind to Tumor cell)

Durvalumab (Imfinzi)

Atezolizumab (Tecentriq)

Avelumab (Bavencio)

CTLA-4 inhibitors (Bind to T cell)

Ipilimumab (Yervoy)

Enzyme inhibitors

Altering the tumor

microenvironment by targeting

enzymes producing metabolites

that activate or impair T cell

response

IDO-1 inhibitors like Epacadostat

are in phase 2/3 studies either as

single agent or in combination

with other immunotherapy agents

Image from O’sullivan et al., Nature Reviews

Immunology volume 19, pages 324–335 (2019)

Cellular therapies “Super Soldiers”

Chimeric Antigen Receptor (CAR) T

cell therapy:

Yescarta and Kymriah targeting CD19

B cell lymphomas are now FDA

approved.

Development of CAR-T cell therapies

a challenge in solid tumors.

Adoptive T cell therapy:

Selected antitumor T cells are

expanded ex vivo and reinfused.

Hot vs Cold

HOT TUMORS COLD TUMORS

High mutation burden Low mutation burden

Tumor infiltrating lymphocytes ↑ Tumor infiltration lymphocytes ↓

Tumor microenvironment immune reactive Tumor microenvironment immune suppressive

Less cancer stem cell plasticity More cancer stem cell plasticity

High PD L1 expression Low PD L1 expression

Immune related adverse events

Postow MA et al. N Engl J Med 2018;378:158-168

Possible Mechanisms Underlying Immune-Related Adverse Events

Postow MA et al. N Engl J Med 2018;378:158-168

PROs

Durable responses

Possible Cure

Better toxicity profile

Good prognostic markers

Wide applicability

Cons

Cold tumor

Hyper-progression

Immune related adverse

events

Expensive

Trials not mature yet