This IL-12 Based Immunotherapy for Dogs Can Turn "cold" tumors "hot"

Can the new IL-12 based immunotherapy help dogs beat cancer? Starting with soft-tissue sarcoma?

A golden retriever, Kinako, lived in Great Falls, Virginia, a member of a large family with four rambunctious kids. She loved going on long walks along the Potomac River and swimming and fetching sticks thrown in the water.

One summer evening, Kinako's mom noticed a slight swelling on the side of her snout.

She took her to the local vet who recommended that she see a cancer specialist.

At South Paws Clinic, a veterinary oncologist ordered tests, and a week later, she was diagnosed with fibrosarcoma, a form of soft tissue sarcoma.

Her family was devastated when they got the news.

Kinako had to get surgery to have the tumor removed. She also received radiation therapy for several weeks so that any remaining tumor cells could be killed.

Her cancer went into remission and she returned to being a happy and active pup, going on outings with her loving family.

But about a year later, as it too often happens with soft tissue sarcomas, cancer began to spread again.

And there was nothing else that could be done to help her.

Sarcomas are a rare cancer for people, but they are extremely common in dogs.

Soft tissue sarcomas originate in the cells of connective, muscle, or nervous tissues and could develop in different parts of the body.

The subtypes include

• fibrosarcoma
• leiomyosarcoma
• liposarcoma
• chondrosarcoma
• synovial sarcoma
• rhabdomyosarcoma

Today's standard of care treatment for soft-tissue sarcoma includes surgery, combined with radiation therapy.

If the cancer cells are not completely removed - especially if they are in locations that make surgery with large margins difficult- the chance of local recurrence for soft tissue sarcoma is very high.

Is there a way to stop the spread of soft tissue sarcoma?

A group of scientists and veterinary oncologists are investigating a new IL-12 based immunotherapy treatments which may help prevent recurrence after surgery.

What's IL-12 ?

IL-12 or Interleukin 12 are cytokine molecules that play a vital role in the immune system.

IL-12 protein molecules are secreted by white blood cells, and can induce potent anti-cancer activity, activating natural killer cells and T-cells that can kill cancer cells.

Why hasn't IL-12 been used before to treat patients with cancer?

IL-12 is so potent that direct introduction can trigger toxic side-effects.

At the doses required to kill cancer cells, it can induce something called "cytokine storm" that could lead to organ damage and even death.

So in 2018, with support from Canine Cancer Alliance, a group of scientists in Seattle began exploring several new, safer ways to introduce IL-12 using gene-delivery methods.

How did they make IL-12 therapy safe?

A quick reminder of how some ,coronavirus vaccines work, using a strand of genetic material called messenger RNA (mRNA).

Our own cells take up these mRNA molecules and make viral spike proteins that can activates the immune system.

In a similar way, it's possible use encode IL-12 proteins in mRNA and have the proteins made by patient's own cells and keep them local to tumors.

IL-12 introduced this way has little danger of causing systemic toxicity, but can still turn a 'cold' tumor microenvironment with little immune activity into a 'hot' tumor environment, with multiple activated immune cells primed to kill tumor cells.

The scientists at a Seattle based biotech called Immune Design actually worked on two delivery systems: one using mRNA and another using safe lentiviral vector that specifically targets dendritic cells . They called the formulation IL12srRNA and ZVex12, respectively.

Here is a link to a publication summarizing their early study.

With support from Canine Cancer Alliance, the researchers at Immune Design and Fred Hutchinson Cancer Research Center worked with local veterinary oncologists to lay the ground work for launching a pilot trial to enroll canine patients with soft tissue sarcoma.

Can patients with soft tissue sarcoma get this therapy?

A clinical trial for this new gene-delivery IL-12 immunotherapy was launched in January 2022 and is enrolling canine patients at the Missouri University Veterinary School.

(Because Immune Design in Seattle was bought by a large pharmaceutical company and key researchers moved to new jobs and different locations, the original team had to re-group. But thanks to the tenacity and vision of Prof. Seth Pollack now at Northwestern University, the clinical trial is now open. )

What are the benefits of participating in this study?

Some of the potential benefits of enrolling in this trial includes:

• By inducing an immune reaction against the tumor cells, this IL-12 therapy may reduce the chance of recurrence and spread of tumor after surgery.
• It's free. Cost of all treatments and checkups are covered by the study. (But the owner does have to pay for the initial eligibility examination)

,Your donation makes these studies possible to help dogs with cancer

What are the eligibility requirements ?

The canine patient must weigh more than 10 kg, and undergo eligibility examination including a blood test, urinalysis, fine needle aspirate of the lesion, CT scan.

No metastatic disease at time of diagnosis. Has not received chemotherapy, radiation or any immunotherapy within 3 weeks of study participation.

An informed consent must be signed, and the participation will require a total of up to 17 visits over a year to the Missouri University clinic.

A summary of inclusion and exclusion criteria is given below. Please contact the veterinary school for the most up-to-date information.

What happens when the dog is enrolled?

The patient will be randomly assigned to one of the two IL-12 gene-delivery studies. (ZVEX12 or IL12srRNA)

Dogs in the ZVex12 study will receive a single injection.

Dogs in the IL12srRNA study will receive four injections one week apart.

All dogs will be monitored before and after each treatment with blood tests, urinalysis, CT scan, as well as a biopsy before therapy. Research blood samples will also be collected.

On day 30, the tumor will be surgically removed.

Dogs will return to the clinic for CT scans at 3 and 6 months, and owners may be contacted up to 2 years to see how the patient is doing.

The information about this clinical trial can be found at the Missouri University Veterinary Health Center page

and in the American Veterinary Medical Association (AVMA) database.

What if the dog doesn't qualify for the IL-12 study?

According to the MU study coordinator, even if a pup does not qualify for the IL-12 immunotherapy trial, the clinic has two additional studies that the patients with sarcoma might qualify for.

• LATTICE SBRT (Stereotactic Body Radiation Therapy)
• Calcium Electroporation Therapy

Learn more at MU Clinic website.

If you found this article helpful, please consider donating. Scientists need your support to find cancer cures.

IL-12 Gene Delivery Immunotherapy Study Summary

Scientific Title:

Novel IL-12 Gene Delivery vehicle for Transformation of Solid Tumors.

Recruitment Dates:

01/02/2022 to 01/01/2024

Primary Study Location:

University of Missouri -- Columbia Missouri

Study Contact Information:

Sydney Miget

[email protected]

1 573 882 7821

Principle Investigator contact:

Prof. Jeffrey Bryan, University of Missouri

Study Description:

This study will test intra-tumor delivery of vectors that produce an immune signaling molecule, IL-12 via injection of ZVex12 or IL12srRNA) to deliver sustained IL-12 production in the tumor to stimulate anti-tumor immunity to treat dogs with sarcoma. ZVex12 and IL12srRNA will both result in an inflammatory sarcoma tumor microenvironment. Through this trial, it is expected that we will determine if increased T cells (anti-tumor immune cells) are present in sarcoma tumors following intra-tumor treatment. Two groups of participants will be assigned by randomization - 3 dogs being injected with ZVex12 (along with ultrasound, if needed) and 3 dogs being injected with IL12srRNA (along with ultrasound, if needed).

Regardless of assigned group, all dogs in the study will be evaluated (to determine eligibility) through blood tests, urinalysis, CT-scan with tumor biopsy, and surgery to remove the tumor.

Inclusion Criteria:

• A high grade soft tissue sarcoma (STS) >4 cm that can be removed by surgery.
• A body weight of >10kg. No significant comorbidities.
• Written informed consent signed by pet owner.
• Adequate hepatic, renal, hematologic function. Adequate bone marrow function, neutrophil count >3000 cells/ml, Platelet count >150,000 cells/ml
• CBC
• Chemistry
• Urinalysis
• CT with RT set-up
• Histologic or cytologic confirmed soft tissue sarcoma

Exclusion Criteria:

• Is a participant in another clinical trial.
• Has a current bacterial infection requiring systemic therapy
• Has received chemotherapy, radiation or any immunotherapy within 3 weeks.

Potential Medical Benefits:

The purpose of the study is to induce an immune reaction against the tumor cells. It is possible that this immune reaction might improve outcome by reducing recurrence and spread of the tumor.

Potential Medical Risks:

Injection will result in an inflammatory sarcoma tumor microenvironment. Since this is a novel approach to treating sarcoma tumors, the total range of possible side effects may not be fully appreciated.

Financial Incentives:

Fully funded after initial screening.

This information was updated on June 13, 2022. For the most up to date information, please check the AVMA animal health studies database or reach out to the named contacts.

IMPORTANT

This blog/article is published for informational and educational purposes only. It is not intended to be a substitute for professional veterinary advice. Always seek guidance from your veterinarian.