Company  Confiden,al  and  Proprietary  

ADXS-NEO Personalized

Neoepitope-Targeted Immunotherapy for

Cancer A convergence of technologies to benefit individual patients

1

Precision/Personalized  Therapies    

Canadian  Organiza,on  for  Rare  Diseases      Annual  Mee,ng  November  7,  2016  

2 Company  Confiden,al  and  Proprietary  2015  Advaxis,  Inc.    |    www.advaxis.com  

The Technologies

Immunotherapy of Cancer •  Immune Systems Role in Tumor Surveillance •  Understanding Immunologic Tolerance •  Manipulating Immunologic Controls •  Understanding Failures and Successes of Immunotherapy

Genomics Science •  Human Genome Project -1988-2003 (International Consortium) •  Molecular Biologic Understanding of Cell Functional Pathways •  High Throughput Massively Parallel DNA/RNA sequencing – Now accomplished in 4-7 days

Oncogenesis •  Why do cells become cancerous •  What drives tumor growth •  Why do people with the same cancer respond differently •  Why does resistance develop

3 Company  Confiden,al  and  Proprietary  2015  Advaxis,  Inc.    |    www.advaxis.com  

The Convergence – A new understanding and treatment paradigm What have we learned?

•  The immune system is generally capable of eliminating cancers

•  The best balance between efficacy and side effects may be immunotherapy

•  Cancers succeed primarily because of a problem or misperception of immune surveillance / tolerance

•  Immunologic activity can be manipulated by pharmaceuticals and/or vaccines

•  Cancer growth is driven by inappropriate signaling within molecular pathways

•  Cancer is caused by an accumulation of mutations, some in tumor growth “driver” genes (10-1000+)

•  Cancer is comprised of a diverse population of variants (not identical cells)

•  Even patients with the same cancer type harbor vastly different sets of mutations

•  DNA sequencing technology is becoming practical, and allows complete understanding of a patients own personal cancer at the genomic and bioinformatics level within a few days

•  The DNA /RNA sequence of a patient’s own cancer is the ultimate personal biomarker

Immuno-Oncology – A History •  1891 William Coley – Coley’s toxins cause tumor regression

•  Inflammatory response to pathogens changes immune tolerance of tumor

•  1985 FDA approves Interferon alpha2b - Hairy Cell Leukemia •  Immune modulation of signaling increases immune resistance against cancer

•  1985 First report of IL-2 LAK adoptive immune therapy (Rosenberg) •  Autologous lymphocytes could be manipulated and cultivated ex-vivo as cancer treatment

•  1988 First Report of Clinical Response to IL-2 TIL treatment (Rosenberg) •  Specific enhancement of CTL’s with tumor reactivity (TILs) more effective

•  Griffith et. al. J. NCI, 81:1709-1717. 1989 Indium 111 labeled TILS.

TILs were trafficking to tumors, but shutting down.

•  1992 Interleukin 2 approved – Metastatic Renal Cancer (1998 Melanoma) •  Agonism of IL-2 receptor stimulate T cell activation and proliferation

•  2010 FDA Approves Provenge – MCRPC •  Directing immune response via dendritic cells can improve survival

•  2011 FDA Approves Yervoy – Advanced Melanoma •  Blocking inhibitory checkpoint facilitates anti-tumor immunity

•  2011 First Report - CD-19 CAR-T in CLL (Carl June)

•  2014 FDA Approves Keytruda – Advanced Melanoma

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~100 Yrs

Adoptive Therapy Meets Tolerance

Tools

Immuno-Oncology Renaissance

Tools

Therapeutic Cancer Vaccines

What makes the best immunotherapies effective?

•  Checkpoint Inhibitors – Temporarily block mechanisms of immune tolerance •  Allows weak immune responses to progress •  CTLA4 – (Yervoy) Melanoma •  PD-1 / PD-L1 – Lung Cancer, Melanoma, Kidney, Head and Neck Cancer, Bladder

•  Opdivo (BMS), Keytruda (Merck), Tecentriq (Roche)

•  TIL Therapy, Rosenberg NCI (and others) – Cell Therapy •  Extract tumor fighting white blood cells from a patient, expand them in the lab, give them back to fight cancer.

5

The  Aha  Moment!  Expansion  of  pre-­‐exis;ng  Tcells  from  the  pa;ent,  that  target  protein  sequences  associated  with  muta;ons  =  “Neoepitopes”    are  responsible  for  long-­‐term  tumor  control    

Company  Confiden,al  and  Proprietary   6  Company  Confiden,al  and  Proprietary  

Mutational Burden by Tumor Type

•  Best efficacy in Melanoma, Lung Cancer •  More Mutations = more chances to have immunogenic neoepitopes (when presented by tumors)

•  Challenge: Tumors are poor antigen presenters, mostly “normal”

•  Solution: Prospectively Immunize patients against their own neoepitopes with a potent system that is highly immunogenic…. Personalized Neoepitope Immunotherapy

Schumacher TN and Schreiber RD. Neoantigens in cancer immunotherapy. Science 2015; 348, 6230: 69-74.

7  

Advaxis – Personalized Neoepitope Immunotherapy

Parallel DNA sequencing mutations identified

ADXS-NEO: Weakened bacteria with neoepitopes

given to patient

Neoepitopes secreted in antigen presenting cells

T cells find, destroy tumor “cell to cell combat”

T cells activated to hunt down neoepitope targets

Neoepitopes presented by patient’s immune system

Neoepitope coding DNA bioengineered into personalized

vector

Immune tolerance reduced

Biopsy  to  first  treatment  ~  6-­‐8  weeks  

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Summary We now have the technology to understand each patient’s cancer at a genomic level

Essentially, every single patient’s cancer is unique with many mutations that cause malignancy

New tools used to control the immune system are making immunotherapy the backbone of new cancer treatments wherever possible

When applied together, technologies can identify the mutations that cause a patient’s cancer, and mobilize the patient’s immune system to those mutations for immune elimination

“Personalized Neoepitope Immunotherapy” uses the very mutations that cause cancer as it’s “Achilles heel”, by training the immune system to target and eliminate the mutated cells

The battle against cancer is a personal one, involving “cell to cell” combat between immune fighter cells and the cancer cells that are trying to evade and neutralize them

Essentially, every cancer patient has a “rare” disease, unique to them alone. However the best way to fight it may be through empowering their own immune system to fight it.

COMPANY CONFIDENTIAL AND PROPRIETARY COMPANY CONFIDENTIAL AND PROPRIETARY

Broad Clinical Pipeline Targeting Multiple Tumors PRODUCT INDICATION PHASE 1 PHASE 2 PHASE 3 Partner

AXAL

CERVICAL CANCER†

MAIM2CERV: Adjuvant Randomized vs Placebo Phase 3*

Metastatic: GOG 0265 Phase 2

C Metastatic: Combo with Durvalumab Phase 1/2

HPV+ HEAD AND NECK CANCER†

M Presurgical: Window of Opportunity – Mount Sinai Phase 2

ANAL CANCER†

M

RTOG: Adjuvant Randomized vs Control Phase 2/3

Adjuvant: Single Arm High Risk – Brown University (BrUOG) Phase 1/2

Metastatic (FAWCETT) Phase 2

ADXS-PSA PROSTATE CANCER

C Metastatic: Combo with KEYTRUDA (pembrolizumab) Phase 1/2

ADXS-HER2

HER2-POSITIVE SOLID TUMORS (INCLUDING OSTEOSARCOMA†)

MMetastatic: Single Arm Phase 1

Osteosarcoma Phase 2

C Combination M Monotherapy Active Planned *Under FDA Special Protocol Assessment. †Orphan Drug Designation.

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305 College Road East Princeton, NJ www.advaxis.com ir@Advaxis.com

Dr. Robert Petit Chief Scientific Officer, EVP