cancer vaccines a primer...summary points • rna-based poly-neoepitope individualized mutanome...

DR TOH HAN CHONG DEPUTY DIRECTOR

NATIONAL CANCER CENTRE SINGAPOREASSOCIATE PROFESSOR

DUKE-NUS MEDICAL SCHOOL

CANCER VACCINES – A PRIMER

WHAT ARE VACCINES?

The Immune System Fights Cancer

HOW CANCER

VACCINES WORK

INFUSE

PATIENT

APC takes

up the

antigen

Recombinant

Prostatic Acid

Phosphatase (PAP)

antigen+GM-CSF

fusion protein binds to

resting antigen

presenting cell (APC)

Fully activated,

the APC is now

Sipuleucel-T

Antigen is

processed and

presented on

surface of the APC

T-cells proliferate and attack

cancer cells

Sipuleucel-T activates

T-cells in the body

Active

T-cellInactive

T-cell

Outcomes of Sipuleucel-T :

• 4.1 months median survival benefit (25.8 months vs. 21.7 months).

• No time to objective disease progression benefit

• No survival difference detected between patients in the sipuleucel-T group who had T-cell responses against PAP and those who did not.

• Vaccine response no correlation with PSA response

Patient 1

Patient 9

Blood

Cytokine

cocktail

Inject DCs

Intradermal

(3-5 x 106 cells/dose;

10 x bi-weekly doses)

QA/QC

FACS,

Endotoxin,

Mycoplasma

testing

DENDRITIC CELL VACCINE FOR COLORECTAL CANCER

TREATMENT OF METASTATIC NASOPHARYNGEAL CARCINOMA WITH AUTOLOGOUS

DENDRITIC CELLS TRANSDUCED WITH ADENOVIRAL VECTOR (AD5F35) EXPRESSING

LATENT MEMBRANE PROTEIN (LMP)-1 AND LMP-2 GENES IN PATIENTS

A Phase II clinical trial, n=16

Blood

Cytokine

Cocktail

(TNFa,IL-1, IL-6, PGE2)

Ad5f35-DLMP1-

LMP2 vector

Intradermal

(3-5 x 106 cells/dose;

5 x bi-weekly doses)

Baseline Date:

24/10/07Date: 5/3/08

PATIENT 004 – PARTIAL RESPONSE

CD40L

MU

C-1

Ad-hMUC-1/ecdCD40L vaccine

DNA

CD40LMUC-1

Fusion protein expression & excretion

Infect

(e.g. fibroblasts)

Fusion protein uptake by DC

DC activation and antigen presentation

Antigen-specific T lymphocyte activation in Lymph nodes

Subcutaneous injection of vaccine

FIRST-IN-HUMAN CANCER VACCINE

MUC1-CD40L VACCINE ON AN ADENOVIRUS BACKBONE

• Oncolytic Virus Therapy gets FDA Approval

Oncolytic Viruses

MORE CANCER MUTATIONS STIMULATE A BETTER IMMUNE RESPONSE

CANCER NEOANTIGENS

Framework for identifying and targeting tumor neoantigens

Mark Yarchoan et al. Nature Reviews. 2017

N = 13, 8 PATIENTS CANCER-FREE PRE-VACCINATION

NEOANTIGEN DISCOVERY TO CLINIC

(A)

(B)2 synthetic RNA vaccine created, each encoding 5 selected peptide variants

T CELL RESPONSES

%

(C) (D)

Summary Points

• RNA-based poly-neoepitope individualized mutanome vaccine against a variety of cancer mutations

• All patients developed T cell responses against several vaccine neoepitopes up to high single-digit percentages

• 8 patients with no disease pre-vaccine remained cancer-free on long follow up

• Of 5 patients with existing disease, 2X had CR (one with anti-PD1 Tx), 1x had PR, 1X had Mixed Response and 1X had SD

Summary Points

• Post-vaccination biopsies from two patients showed evidence of vaccine-induced T cell infiltration and neo-epitope-specific killing of autologous tumor cells

• One patient with metastatic disease developed a complete response to vaccination in combination with PD-1 blockade therapy even after rapid progression post-vaccine

• One patient with PR had a late relapse due to outgrowth of β2-microglobulin-deficient melanoma cells as an acquired resistance mechanism

NEOANTIGEN PEPTIDE VACCINE

NEOANTIGEN PEPTIDE VACCINE

• Vaccine targets 13 to 20 predicted personal tumour neoantigens, selected for HLA Class I binding

• CD4+ and CD8+ T cells targeted 97 unique neoantigens used across patients, and 60% T cell responses were CD4 T cell mediated

• Six vaccinated melanoma patients

• Two patients with disease pre-vaccine had CR in combo with anti-PD1 Tx, the four with no prior disease remained disease-free

rational combinations with cancer vaccines

BEWARE OF FALSE CANCER TREATMENT CLAIMS