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Can A New Adoptive Cell Immunotherapy Induce Long-term Remission in Dogs with Osteosarcoma?
Key Points
A new cancer treatment based on immunotherapy developed by ELIAS Animal Health is currently available for osteosarcoma patients.
In the clinical trial, half of the ten dogs that completed the therapy became disease-free and experienced long-term remission.
The treatment includes vaccination and T-cell infusion, and is a form of vaccine-primed adoptive cell therapy.
Wouldn't it be wonderful if remission from canine osteosarcoma meant years of ball-chasing, tail-wagging and living a dog's best life?
Osteosarcoma is one of the most aggressive type of canine cancer. Even with amputation and chemotherapy, the survival time is typically less than a year. Having lost our dog, Gus, to osteosarcoma three years ago, I've been particularly interested in research for new treatments for this disease.
Like many dogs, Gus ended up with pulmonary metastasis 12 months after his diagnosis, and my big disappointment was not being able to enroll him in a immunotherapy clinical trial for a shot at a long-term remission.
Immunotherapy engages the immune system to fight cancer and has produced outstanding results in some human patients.
After losing Gus, I wanted to learn as much as possible about research in dog cancer treatments. So in early 2018, I flew to Anchorage, Alaska, to attend a Veterinary Cancer Society conference, which is where I first learned about a new immunotherapy developed by ELIAS Animal Health and began following their work.
Recently, they reported findings from their clinical trial so I reached out to their founder and CEO Tammie Wahaus, and their Chief Medical Officer Noel Reyes DVM to learn more. I also had a conversation with Prof. Jeffrey N Bryan DVM Ph.D., who led their clinical studies at the University of Missouri.
Here is a summary of what I learned.
What is ELIAS Cancer Immunotherapy or ECI®?
Elias Cancer Immunotherapy or ECI is a form of immunotherapy known as Autologous Adoptive Cell Therapy or Adoptive T-Cell Therapy.
A dog's cancer-fighting T-cells are removed and activated in the laboratory and infused back into the dog so they can better kill cancer cells.
ELIAS combines it with vaccination. They produce a vaccine using the dog's own tumor cells, so the immune system is first stimulated to recognize the unique proteins on the surface of the tumor cells.
A form of Adoptive Cell Therapy called CAR-T therapy has met with spectacular successes with some human patients with blood cancer.
How does it work?
ECI treatment is administered over 6-8 weeks and consists of two steps.
Step 1
The patient dog undergoes amputation surgery of the affected limb. A tumor sample is sent to ELIAS's lab, where a vaccine is created. This patient-specific vaccine is injected intradermally weekly for three weeks.
The goal of this step is to increase the number of primed T-cells that specifically target cancer neoantigens in the patient's body. (Neoantigens are new antigens or proteins formed by cancer-specific mutations and found on the surface of tumor cells).
Step 2
The white blood cells are removed from the patient in a procedure called apheresis. It takes 4-6 hours depending on the size of the dog and requires sedation.
The collected white blood cells are sent to ELIAS's lab.
In the lab, mononuclear white blood cells are stimulated using a T cell-specific super-antigen. The vaccine-primed precursor T-cells are differentiated and activated into effector T-cells that can attack cancer.
These activated T-cells are shipped back to the clinic where, roughly seven days after apheresis, the patient receives an infusion of the T-cells.
The dog also receives five subcutaneous IL-2 injections. IL2 is an immune-stimulating cytokine (molecules usually secreted by cells) and helps sustain in-vivo T-cell proliferation.
What do we know about the safety of the treatment?
ELIAS has been evaluating ECI for several years by working with different veterinary teaching hospitals and clinicians.
In a trial recently described in a scientific conference paper, a total of 14 dogs with osteosarcoma were enrolled and evaluated.
The dogs included lab retrievers, few golden retrievers, and Great Danes. The median age was 6.6 years old, and the median weight was 39 kg (85lb).
Ten out of fourteen dogs completed the entire treatment protocol.
For all dogs, the treatment proved to be very safe and the observed side effects were mild to moderate and transient.
What is the standard-of-care treatment for dogs with osteosarcoma and does this immunotherapy treatment extend survival times?
Standard-of-care treatment for many osteosarcoma patients consists of amputation surgery followed by chemotherapy. And ECI’s median survival time was greater than historical survival times for dogs receiving surgery and chemotherapy treatment.
The median survival time for dogs getting surgery (without chemotherapy) is 134 days.
The median survival time for dogs receiving surgery+chemotherapy is 308 days.
ELIAS reported a median survival time of 415 days for dogs who had surgery + ECI. (No chemotherapy)
This means that half the dogs who finished their treatment survived beyond 415 days.
The survival times and quality of life have been impressive for some dogs, according to ELIAS.
However, we have to remember that n is still very small in their trial.
So their findings do not mean that roughly half of the dogs receiving the treatment are guaranteed to experience long-term remission.
A larger clinical trial is being planned, so they can better understand the efficacy and safety of the treatment.
What do we know about how different dogs responded to the treatment?
Five of the ten dogs that completed the treatment were still alive and disease-free at the time of the conference paper at the end of 2019.
Were any dogs with metastasis enrolled in the trial?
The trial excluded dogs with metastasis during enrollment. But according to researchers at the University of Missouri, one dog, Titan, developed pulmonary metastasis shortly after T-cell infusion. They noted that his metastasis progressed very slowly, and he led a very active life for an additional six months with metastatic disease.
Also, another dog, Roscoe, developed metastasis after his treatment was completed.
What happened to Roscoe?
Roscoe, a Dane, was diagnosed with osteosarcoma in May 2017 when he was six years old. His leg was amputated, and he received ELIAS' immunotherapy partly because his parents did not want him to get chemotherapy.
Soon after the infusion, he developed a subcutaneous mass that was confirmed to be osteosarcoma metastasis. The researchers assumed that he was not going to survive, but when they followed up with Roscoe's parents several months later, they were delighted to learn that Roscoe was still alive.
Roscoe experienced full regression of metastasis and is still alive today (Feb 2020).
According to Dr. Noe Reyes DVM,
"It is important to note that not all dogs will respond this well as there is a complicated interaction going on that is dependent on the patient's immune system health and the aggressiveness of cancer, among other things.
But when we do see a response, it has been quite substantial and sometimes complete.
Some of the results seen are similar to those observed in human CAR-T patients (for example, when it works, it can have dramatic results).
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Are some of the dogs cured?
One dog lived disease-free for 30 months until developing metastasis and was euthanized. Such case highlights the reason why clinicians are often very hesitant to claim that any cancer patient is "cured".
For some dogs, it is an ongoing battle between their immune system and the cancer cells.
What kind of side effects did the dogs experience?
All the side-effects were minor and were relieved with the help of anti-nausea medication, NSAIDs, and antihistamines.
Following the vaccination, some dogs experienced inappetence, lethargy, and vomiting but the symptoms went away in 1-2 days. After adoptive T-cell infusion, some dogs experienced fever, diarrhea, lethargy, and inappetence.
With a larger clinical trial, we will find out how different dogs will respond.
Is the therapy available for dogs today?
Yes, ECI is available for new osteosarcoma patients thanks to USDA's 9 CFR 103.3 experimental product regulations.
What are the requirements for the dog to receive this immunotherapy?
The dog needs to have a diagnosis of osteosarcoma.
It is not recommended for dogs with metastasis.
The dog should not be on any immunosuppressive drugs, like steroids.
Other than cancer, the dog should be in good health.
Able to travel to the clinic to receive all the vaccination, apheresis, infusion, and injections.
Please check with the veterinarian for a complete list.
Can a dog receive this treatment without surgery
Today, the protocol is designed to include amputation so that the patient has a minimal residual disease, and the immune system will have the best opportunity for success.
In the future, it may be possible to evaluate the treatment without amputation using a biopsy to obtain tumor cells to manufacture the vaccine.
Can a dog with cancer other than osteosarcoma receive the treatment?
Not today. ELIAS is planning to evaluate this therapy in other cancers, and pilot studies for other cancer types may start later in 2020.
How can I find out which clinics are offering the treatment today?
ELIAS's website lists locations and participating veterinarians. If a clinic nearby is not on the list, I recommend contacting ELIAS directly to ask. New clinics are being added, and the website may not reflect the most up to date information. For example, a clinic 10 miles from my home is not yet on the list. However, I know that they are working with ELIAS to be added.
How much does this treatment cost?
The treatment costs slightly more than chemotherapy and will depend on the clinic. A number that I heard mentioned is $10,000+.
Does pet health insurance cover this treatment?
Because it is still an experimental therapy, it is not covered by most veterinary pet insurance. But it is hoped that insurance will include it in the future.
When we were caring for our dog, even after paying for surgery and chemo, we continued to spend $500-1000 per month for additional exams, herbal supplements, acupuncture sessions, etc. So in total, we spent close to $15K, which we were lucky enough to be able to do at the time.
If I had to choose today, I would most likely select this immunotherapy over traditional chemotherapy because I believe my dog would get a chance at a more durable remission. (And I would explore other immunotherapy options)
But that's my personal opinion, and each pet owner's situation is different.
In addition to financial consideration, it may be hard to take time off and travel distances if the clinic offering the treatment is far away. The decision is difficult, especially because this is still an experimental treatment, and there is no guarantee that the dog will respond well to the therapy.
Thank you for reading! Please leave any comments or questions down below, and I will try our best to answer them. You can also send me a message at mmaeda@ccralliance.org
ADDITIONAL INFORMATION
For those interested, you will find more information including ELIAS's future clinical trial, and applications to other cancer types and to human cancers below. I also list several other experimental immunotherapy treatments.
Where is this treatment in terms of commercialization?
The treatment is approved for experimental use by the USDA (US government regulatory body), so they are offered by approximately 30 clinics in the US today.
ELIAS will need to conduct a new clinical trial (known as a "pivotal trial") with many more participating dogs so the treatment can become a fully approved, licensed commercial therapy.
Therefore soon, pet parents will have an option of getting the treatment from a clinic, or enrolling him in a new clinical trial with subsidized treatment costs.
If my dog is treated with ECI now, is he automatically enrolled in a new clinical trial?
No. Clinical trial plans are still in development, and while the details have not yet been shared, it may end up being a randomized trial with a control arm. That means that half of the dogs will be randomly assigned to get the immunotherapy treatment while the rest of the dogs may receive conventional therapy, such as chemotherapy.
When and where will the clinical trial open?
Location(s) are still to be announced. It is expected to open in the first half of 2020 for osteosarcoma patients.
What are the advantages of enrolling in the new clinical trial?
-Treatment costs are less since it will be partly subsidized by ELIAS.
-As part of a formal clinical trial, you and your dog will be helping advance scientific research, which will translate to saving lives of many more dogs in the future.
What are the disadvantages of enrolling in the clinical trial?
-Not known when the new trial will begin and which hospitals are involved
-The inclusion criteria may be more stringent.
-If the new trial is a randomized trial, your dog may end up being assigned to the control arm and not receive the immunotherapy.
Can this treatment work for other cancer types?
The hypothesis is that it will work for different types of cancer.
It appears that ELIAS did conduct a small safety trial with B-cell Lymphoma patients several years ago.
But I have not seen any published data of the results.
ELIAS shared that they are planning to start pilot studies in 2020 for oral melanoma and Transitional Cell Carcinoma (a form of bladder cancer).
Are there other adoptive cell therapy trials for canine patients?
Yes. Aurelius Biotherapeutics in Bellingham, WA, is offering adoptive T cell therapy for B-cell lymphoma canine patients. But little data has been published for this trial.
Are there other cancer-fighting vaccines available for canine patients?
Yes. And they are both less expensive options.
Yale University School of Medicine team is testing their HER2/EGFR vaccine with canine patients with osteosarcoma, hemangiosarcoma, and several other cancer types.
Torigen Pharmaceuticals is conducting a trial offering autologous vaccines for dogs and cats. Their trial is for pets with: anal sac adenocarcinoma, fibrosarcoma, mast cell tumors, melanoma, soft tissue sarcoma, and carcinoma (basal cell, hepatocellular, nasal, mammary, squamous cell).
What are the mission and the background of ELIAS Animal Health?
ELIAS Animal Health is a company with a mission to develop veterinary cancer immunotherapy treatments. They are located near Kansas City.
The company was launched in 2014 as a subsidiary to TVAX Biomedical and then spun off to a group of investors in 2015. TVAX focuses on the development of cancer treatments for human patients.
Who is funding their trials?
They are funded by ELIAS Animal Health, which had raised investment funds of $7.6million for their work.
Is this treatment available in a clinical trial for human patients, including osteosarcoma?
Not yet. But TVAX Biomedical, ELIAS' affiliate company, is raising funds to start a 75-person trial for glioblastoma patients based on successful data they had from an earlier human trial.
What do we know about this treatment applied to human patients?
According to an early publication, vaccine-enhanced adoptive T-cell therapy was used to treat nineteen patients with recurrent malignant glioma. Immune response was detected in many patients. The median survival was 12 months (range 6-28 months).
While this number looks modest, most of the patients in this old study had recurrent aggressive glioma, with previously failed treatments. If treated earlier, it is possible that the treatment will induce long-term remission.
It would be amazing and wonderful if this treatment helps brain cancer patients; their options are so limited today.
Sources
T Wahaus, N Reyes, J Bryan, G. Wood, B Flesner, L Donnelly, D Tate, "Prospecdtive translational study evaluating vaccine-enhanced adoptive T cell therapy for treatment of osteosardoma in companion dogs", SITC 2019 Poster Paper.
A Sloan, etal, "Adoptive immunotherapy in patients with recurrent malignant glioma: preliminary results of using autologous whole-tumor vaccine plus granuocyte-macrophage colony-stimulating factor and adoptive transfer of anti-CD3-activated lymphocytes." Neurosurgical Focus 9, 2000.
TVAX BIomedical Website Presentation.
Tripawds.com website story and interview of Dr. Jeffrey Bryan
More about Roscoe the Great Dane here
An interview with Dr Jeffrey Bryan of University of Missouri who led the last clinical trial here.