Weaponizing Immune Cells with New Liposomes to Target

D-6332| Immuno-based Targeted Cancer Therapy| 8/2018

Weaponizing Immune Cells with New Liposomes to Target

Metastatic Cancer

Dr. Michael KingCornell University


90% of cancer related deaths occur due to metastasis1.

Cancer Metastasis

1Chaffer et al, A perspective on cancer cell metastasis. Science, 2011

When tumor cells detached from the primary cancer to enter the lymph system and/or bloodstream Stage 3 or 4 cancer


Unmet Need: Prostate & Colorectal Cancer

Prostate Cancer• Second most diagnosed cancer

globally• 1.1 million men diagnosed in 2012• At diagnosis, 21% of cases have

metastasized• 5yr survival rate for late stage

metastatic disease is 29% in U.S.

Metastatic form of both cancers are incurable, have limited treatment options, and are associated with a poor prognosis

Colorectal Cancer• Third most diagnosed cancer

globally• 1.2 million cases diagnosed in 2015• At diagnosis, 25% of cases have

metastasized• 5yr survival rate for late stage

metastatic disease is 11% in U.S.

While effective therapies exist to treat primary tumors, treatments to slow/stop metastasis remain ineffective


Current First-line TreatmentsFirst-line treatment is used for stage 1 or stage 2 cancer, which is localized and has not spread or metastasized

Standard treatment options

Prostate cancer: chemotherapy, cryotherapy, radiotherapy, hormone therapy, and surgery

Colorectal cancer: chemotherapy, radiotherapy, and surgery

Options for early stage prostate and colorectal cancer are limited and have low specificity for cancer cells, along with high toxicity for healthy cells, organs, and tissues.

What about standard treatment options for advanced cancer(stage 3 or 4) that has spread throughout the body?


Competitive Landscape:1/Second-line Treatment for Advanced, Metastatic Prostate Cancer

Treatment Drugs: FDA approval date

Efficacy in Clinical Trial

Leukapheresis Cancer cell Specificity

Toxicity Mechanism of action

Cost

Cellular Immunotherapy Provenge: 2010 Overall survival

benefit Yes High Low Immunostimulant $100,000/month

Bone Metastases(Bisphosphonates) Xgeva: 2010

Prevention of skeletal related

eventsNo High Low Monoclonal

antibody $1,650/injection

Hormone therapy

Xtanti: 2012Zytiga: 2011

Degarelix:2008Flutamide: 2001

Lupron, Nilandron, Casodex, Zoladex:

1997-1989

Overall survival benefit No Low

Low-highdepending

on drug

Blockeffect/release of

hormones

Xtanti: $7,450/monthZytiga: $5,000/monthDegarelix: $4,411/yr

Flutamide: $226/125mg

Chemotherapy Jevtana: 2010Taxotere: 1996

Increase median survival No Low High Stop cell division

$23,000/month$15,000/10 cycles

Radiation therapy Xofigo: 2013Extends life for

about 3.5 months

No Low Moderate Alpha radiation $69,000/6 injections


Competitive Landscape:2/ Second-line Treatment for Advanced, Metastatic Colorectal Cancer

Treatment Drugs: FDA approval date

Efficacy in Clinical Trial

Leukapheresis Cancer cell Specificity

Toxicity Mechanism of action

Cost

Monoclonal antibodies

Cyramza: 2014 Erbitux: 2009Vectibix: 2006Avastin:2004

Extended life No HighLow-Moderate

if used with chemotherapy

Inhibits or blocks the growth of

blood vessels

$5,100/500mg$80,000/18 wks$2,000/infusion

≥ $55,000/yr

Immunotherapy Opdivo: 2014 Overall survival benefit No High Moderate

Immune checkpoint

inhibitor

$150,000/yr

Chemotherapy

Lonsurf: 2015Eloxatin: 2005Camptosar and

Xeloda:1996-1998

Overall survival benefit No Low High Induces DNA

damage

1. Lonsurf: $10,947/cycle

2. Eloxatin: $92/50mg

Protein inhibitorZaltrap: 2012Stivarga: 2012 Overall survival

benefit No High Low-HighInhibits bloodvessel growth

$11,000/month$16,321/40mg

Limited treatment options that vary in cancer cell specificity, toxicity, and cost


Cornell InventionMethods: Coating of immune cells with a cancerspecific cell death inducing agent (TRAIL)

1. Coating of immune cells with liposome containingTRAIL; process can occur in-vivo (method 1, topimage) or in-vitro and then introduced into thebody (method 2, bottom image)

2. Introduce liposome-immune complex intobloodstream and/or lymphatic system of patients

3. Immune cell/TRAIL complex will target and kill thecirculating tumor cells (CTCs) it comes into contactwith inside the body

4. Killing of CTCs will prevent cancer metastasis

Two different types of TRAIL containing liposomeshave been created to date to attack metastatic,CTCs. See schematic on next slide

Method 2: in-vitro Functionalization

Method 1: in-vivo Functionalization

Presenter

Presentation Notes

Figures adapted from Klebanoff et al., Immunotherapy, 2014


Schematic of Cornell LiposomesMetastatic cells

inside lymph nodes

Liposome

Leukocyte

TRAIL

Death receptor 4/5

E-selectin ligand

LiposomeAnti-NK1.1

Natural killer cell

TRAIL

Death receptor

NK1.1

Metastatic cells inside bloodstream

Death of circulating tumor cells

4/5

E-selectin


Mechanism of Cancer Cell Elimination• Cornell liposomes contain cell death inducing agent (TRAIL) which preferentially kills

tumor cells and not normal cells


Major Advantages of Cornell Liposomes

• Repurposing of leukocytes in flowing blood is moreeffective than directly targeting the cancer cells with justliposomes or soluble proteins

• Liposomes are attractive drug carriers that have beenbroadly tested and are considered safe (See additionaldata)

• Mimics membrane-bound TRAIL which has enhancedpro-apoptotic effect Cornell liposome attaches to

immune cell; half life ~ 30hrs

Immune cellTRAIL


Applications of Cornell Liposomes• Can be used:

– At late stage as second-line treatment (stages 3-4)

– At early stage (stages 1-2) in combination of with a first-line treatment

– Before or after surgery to prevent metastases of detached cancer cells from primarytumor

• Advantages over other TRAIL therapy (See additional data)

– Increased bioactivity (greater stability and maximal crosslinking of TRAIL receptors)

– High specificity for tumor (e.g. targeting moieties) due to attachment to immune cells

– Can be used for solid tumors and Cornell liposomes used at late stage of cancerdevelopment may still be effective at reducing CTC numbers

– Exhibit longer half-life than other nanoparticle formulations of TRAIL


Proof of Concept: in-vivo Testing for metastatic prostate & colon cancer

• Cornell liposomes eliminate circulating tumor cells inbloodstream & lead to dramatic reduction in primary tumor.


Summary of Cornell Liposomes

Potential for fast track designation

Metastatic Route

Functionalized Immune cell

Cornell Liposome

In-vivo testing in mice models

Advantages

Bloodstream Many immunecell subsets

TRAIL andE-selectin

Prostate cancer Increased circulation time

LymphaticSystem

Natural killer (NK) cells

TRAIL and antibody for NK

cells

Colon cancer Enhanced retention time in lymph nodes


Intellectual Property

• “Method to functionalize cells in human blood, other fluidsand tissues using nanoparticles”– Patent application filed in the U.S. publication number 2016-0184395– Licensing rights available for all Field-of-Use

Licensing Contact

Jeff FearnSenior Technology Licensing [email protected]

https://patents.google.com/patent/WO2015017854A1/en


The Lead Inventor

Michael King (Profile link)• Adjunct Professor, Cornell Biomedical

Engineering• Expert in cellular engineering, drug

delivery, and nanotechnology

https://www.bme.cornell.edu/people/profile.cfm?netid=mrk93_eng


ADDITIONAL DATA


FDA approved liposomes as cancer drug delivery system

FDA Approval Date Active Agent Indication Company

Doxil (1995) Doxorubicin Ovarian, breast cancer, Kaposi’s sarcoma Sequus Pharmaceuticals

DaunoXome (1996) Daunorubicin AIDS-related Kaposi’s sarcoma NeXstar Pharmaceuticals

DepoCyt (1999) Cytarabine/Ara-C Neoplastic meningitis SkyPharma Inc.

Myocet (2000) Doxorubicin Combination therapy with cyclophosphamide in metastatic breast cancer

Elan Pharmaceuticals

Mepact (2004) Mifamurtide High-grade, resectable, non-metastatic osteosarcoma Takeda PharmaceuticalLimited

Marqibo (2012) Vincristine Acute lymphoblastic leukemia Talon Therapeutics, Inc.

Onivyde (2015) Irinotecan Combination therapy with fluorouracil and leucovorinin metastatic adenocarcinoma of the pancreas

Merrimack Pharmaceuticals Inc.

Vyxeos (2017) Daunorubicin and Cytarabine

Newly-diagnosed therapy related-AML or AML with myelodysplasia-related changes

Jazz Pharmaceuticals, Inc.

Adapted from Pharmaceutics 2017, 9, 12; doi:10.3390 pharmaceutics9020012

Liposomes are attractive drug carriers that have been broadly tested and are consideredsafe


Advantages of Cornell liposomes over other TRAIL therapyTRAIL based

therapiesToxicity Cancer Test in

Phase 2Safety Cancer Cell

SpecificityHalf-life Clinical Trial Results

(Phase 2) Shortcomings

Recombinant soluble agonist

Dulanermin : TRAIL-DR4/5Low Lung and Lymphoma High Low Short (hours) No anticancer activity in

RCT

• Weak agonists • Primary cancer may be resistant to

TRAIL monotherapy• Short half life• Rapid clearance from circulation

Agonistic antibody

Mapatumumab:TRAIL-DR4

ConatumumabDrozitumumab

Lexatumumab, TigatuzumanLBY-135: TRAIL-DR5

Low

Multiple Myeloma, Lung, soft tissue sarcoma, lung,

pancreatic, colorectal,

High Low Long (days-wks)

No anticancer activity in RCT

• Targets only one TRAIL receptorbivalent antibodies need further crosslinking

• Weak agonists• Primary cancer may be resistant to

TRAIL

TRAIL based liposomal

nanoparticlesTAS266: TRAIL-DR5Others not tested

High Terminated at Phase 1 Unknown Unknown Unknown Terminated at Phase 1

• Potential hepatotoxicity• Strong immunogenicity• Primary cancer may be resistant to

TRAIL

Cornell Liposome Low(1) Not testedHigh

In-vivo in mice

High 30 hours in mice Not tested Not tested

Cornell liposomes have increased bioactivity, enhanced cancer specific targeting due to attachment to immune cells, and can be used for solid tumors and CTCs

(1) Avi Ashkenazi and Roy S. Herbst. (2008). To kill a tumor cell: the potential of proapoptotic receptor agonists. J Clin Invest.118(6):1979-1990. doi:10.1172/JCI34359.

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Weaponizing Immune Cells with New Liposomes to Target