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