Cancer immunotherapy in veterinary medicine: Current options

and new developments

Indian Veterinary Research InstituteDivision of Veterinary Medicine

MonikaM-5626

Contents

1 •Introduction

2 •Active and passive immunotherapy

3 •Obstacles

4 •Various approaches

5 •Conclusion

• Immunotherapy is a new class of cancer treatment that works to harness the innate powers of the immune system to fight cancer.

• Also called as biologic or biotherapy

• Fourth arm to treat cancer

Why immunotherapy

Powerful

Specific

Universal

Memory

Active immunotherapy

Seeks to elicit an anti tumor response from the patient’s

own immune system, typically through vaccination

Different approaches..

Obstacles....

Immunoedi

ting by cancer

ous cell

EliminationEquilbrium

Escape

( Anderson et al.,2015)

(Regan et al.,2016)

The tumor microenvironment evolves to create a highly immunosuppressive barrier that limits the effectiveness of an immune response

Suppression of T-cell by by expressing PD-1L

Monoclonal Antibodies

mAbs are designed to modulate targets expressed on the surface of cancer cells or

in the tumor microenvironment mAbs that

directly bind to malignant cells

mAbs that act to block growth-

promoting pathways in the tumor stroma mAbs, termed

immune checkpoint inhibitors

(Jaime et al.,2015)

Rituximab (Rituxan)

• Anti-CD20• First mabs• Approved from FDA• Treatment of both hematologic and solid

malignancies• Successful treated B cell lymphoma in dogs• 1mg/ml, i/v infusion in 0.9% NaCl, 2 doses two weeks

apart

(Vacchelli et al.,2014)

AT-005

mAb targeting CD52 on T cells

conditional approval from the USDA

for the treatment of T cell lymphoma

currently being tested in canine clinical trials

(Aratana et al.,2015)

cetuximab

•Anti-EGFR•Used in epithelial cancers

Transtuzumab

•Anti- HER2•Used in canine mammary carcinoma

mAbs used in the treatment of solid malignancies

(Bethge et al.,2004)

• available as Erbitux

•5mg/ml infusion, 5mg/min

•Not more than 120 minutes

•400mg/m2 once in a week followed by 250mg/m2

Monoclonal Antibodies That Block Growth-Promoting Pathways in the Tumor Stroma

Bevacizumab

mAb against vascular endothelial growth factor (VEGF)

improves the infiltration of effector T cells into the tumor

therapeutically efficacious in inhibiting the growth of canine sarcomas

(Huang et al.,2014)

Immune Checkpoint Inhibitors

• yet to be tested in canine clinical trials

• expression of canine PD-L1 has been detected on a number of canine tumor types, including mastocytoma, melanoma, renal cell carcinoma

(Maekawa et al.,2014)

Immunoconjugates and Other Modified Antibodies

Currently two ADCs, brentuximab

vedotin (against the CD30

antigen expressed in some lymphocytes) and

trastuzumab emtansine

(Peters et al.,2015)

In Situ Immunization with Adenovirus-Fas Ligand

promote inflammation and necrosis at the primary tumor site

This therapy has been used to treat a variety of melanomas and canine osteosarcoma

The potential for systemic or chronic toxicity is reduced by the self-limiting nature of AdFasL therapy

This approach induces supraphysiologic FasL expression in both tumor cells and cells in the local microenvironment to enhance therapeutic efficacy

Modiano et al.,2004

Anderson et al.,2015

Administration of Attenuated Bacteria

non-specific stimulants of the innate immune system

Genetically modified facultative anaerobic bacteria such as Salmonella typhimurium, Listeria

monocytogenes,Corynebacterium and BCG are used

induce tumor cytotoxicity, to disrupt the tumor microenvironment, and to stimulate an anti-tumor

immune response

One final benefit of this therapy is the ability to control these agents with antibiotics in the case of

therapy-related adverse events

(Wood et al.,2014)

Oncolytic virotherapy

• Oncolytic viruses (OV), which preferentially infect and lyse cancer cells

• Adenoviruses, morbiliviruses, reoviruses, and poxviruses

• Oncolytic viruses were originally designed to induce “acute tumor debulking” following direct lysis of the tumor cells

• China approved the use of a recombinant adenovirus (Oncorine)

(Lichty et al.,2014)

Adoptive T cell transfer• In adoptive cell therapy (ACT), autologous T cells are

expanded and activated or modified ex vivo before being re-infused into the patient, thus circumventing tumor-induced immunosuppression

• Currently, three forms of ACT are being developed for clinical use

a) Tumor-infiltrating lymphocyte (TIL) therapyb) T cell receptor (TCR) engineered T cells,c) Chimeric antigen receptor (CAR) T cells

(June et al.,2015)

Anti- cancer vaccines

• Therapeutic cancer vaccines utilize a variety of approaches to induce immune activation including the injection of:

- whole cell or tumor cell lysates- peptide antigens, plasmid DNA, - activated immune cells primed with tumor

antigens • Depends upon TAAs

(Bergman et al.,2007)

The first therapeutic cancer vaccine to be

approved for any species was the

xenogeneic DNA vaccine Oncept which was approved by the

USDA for use in canine oral

melanoma in 2007

Another genetic vaccine that has been pursued in canine clinical trials encodes a catalytically inactive form of dog telomerase reverse transcriptase (dTERT)

(Peruzzi et al.,2010)Bergman et al.,2006

S/c route

Administer five injections (each approximately 0.2 ml) around the tumour excision site: one

injection at each corner and one injection at the centre of a 5 cm x 5 cm square centred on the

middle of the surgical scar.

Treatment course: 4 administrations at 1-week intervals (day 0, day 7, day 14, day 21) followed

by 2 administrations at 2-week intervals Start the treatment course the day before

radiation therapy, preferably within one month after surgical excision.

• The current challenge in cancer vaccination lies in understanding and overcoming immune system dysfunction, either through improved vaccination strategies or by combining vaccination with other treatment modalities

(Mulders et al.,2015)

(Zitvogel et al.,2015)

• Inhalational administration of human IL-2 has also been shown to generate significant antitumor activity in dogs with lung metastases.

(Khanna et al.,1996)

Innate Immune Activation by Recombinant Cytokines

The innate immune system can also be activated by administration of cytokines, including IL-2, IL-12, IFN-γ, IFN-α and TNF-α

INF-α has been used for immunotherapy of cancer in dogs and in cats for squamous cell carcinoma

CLDC (cationic liposome-DNA complex) on i/v administration also stimulate NK cells and contol growth of canine osteosarcoma. This compound is currently evaluated for

use in veterinary immunotherapeutic in Europe

(Dow et al.,2006)

IL-12 electrogene therapy resulted in significant delay in TVT cases by increasing tumor infiltrating lyuphocytes.

(Pavlin et al.,2011)

Liposomal clodronate (LC) has been evaluated as a cancer immunotherapeutic in dogs

Liposomal

encapsulated drug

Taken up by these

macrophages

Cytoplasmic drug release

Rapid induction

of apoptosis

(Hafeman et al.,2010)

(Regan et al.,2015)

(Guth et al.,2013)

An alternative strategy for eliminating tumor macrophages is to selectively block the migration and recruitment of inflammatory monocytes to tumor tissues

•CCL2 major chemokine produced by tumor•certain classes of drugs (e.g., angiotensin-receptor blocking agents such as losartan) can also block CCL2 dependent migration of canine monocytes in vivo and in vitro.

• The NLR agonist MTP (administered as a liposomal formulation known as L-MTP-PE) is demonstrated anti-metastatic activity in canine osteosarcoma

• L-MTP-PE (Mifamurtide) is only available for use in Europe

(Kurzman et al.,1995)

Depletion of Tregs

•Increases in various tumors like lymphoma and carcinomas

(Biller et al.,2010)

•Tyrosine kinase inhibitor has been found to deplete Tregs-Toceranib-Sunitinib

(Duffy et al.,2010)

(Regan et al.,2015)

Cont....

conclusion

Mabs therapy represent one of the most promising avenues for the development of veterinary immunotherapy

Veterinary trials also represent opportunities to develop improved therapeutic modalities, optimize dosing schedules, identify biomarkers to

predict and identify responses

Veterinary clinical trials have the ability to not only improve the lives of our patients, but to uniquely inform human clinical trials

these therapies do not need to be personalized for each individual patient i.e “off the shelf”.