Chemotalk Newsletter

Chemotalk Newsletter, Vol. 104 December 1, 2016

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Well...it's the end of one the year.  Finally.  So let's make it interesting...

NEW TRICKS IN CANINE CANCER RESEARCH MAY IMPROVE TREATMENTS FOR HUMANS

By Laurie McGinley

Harley, a 4-year-old boxer who has LEUKEMIA, receives an infusion of his own T cells at the University of Pennsylvania’s Ryan Veterinary Hospital. The cells have been genetically modified to help combat his cancer.

Flyer, a 70-pound golden retriever, lies patiently on her left side on an examination table as technicians scurry around, placing little sandbags on her legs and neck to keep her still. She’s getting chest X-rays to answer a critical question: Has a deadly BONE CANCER spread to her lungs?

When the session is over, Martha Maloney Huss, a veterinarian at the University of Pennsylvania’s Ryan Veterinary Hospital, glances at the images. “I don’t see anything hugely obvious,” she says, “but we’ll see what the radiologist says.” Oblivious to the good news, Flyer hops down the hall on three legs, eager to find her owner.

After the 8-year-old retriever began limping last year, she was diagnosed with OSTEOSARCOMA, a painful, aggressive cancer that often strikes Great Danes, Irish wolfhounds and other large breeds. At Penn Vet, she got the standard treatment: One of her left legs was amputated, and she underwent CHEMOTHERAPY.

Yet even as she adjusted to chasing squirrels, her prognosis was bleak. Most dogs die in about a year when the disease resurfaces in the lungs. The Penn vets recommended an experimental vaccine designed to prevent or delay the cancer’s return; Flyer’s owner was enthusiastic. The dog got three intravenous doses as part of a clinical trial and now returns to Penn periodically for X-rays.

“Every day I pray that she will stay cancer-free,” said her owner, Bob Street, who lives in Mullica Hill, N.J. “And that this treatment will work for other dogs and for people."

Flyer is part of a burgeoning field called “comparative oncology.” It focuses on finding new ways to treat cancer in pets, mostly dogs, in an effort to develop innovative treatments for people and animals.

The growing interest in dogs reflects researchers’ frustration with the standard approach to developing cancer treatments: testing them in lab animals, especially mice. Mice don’t normally get cancer — it must be induced — and the immune systems in many strains of lab mice have been altered. That makes them especially poor models for immunotherapy, a rapidly growing field of medicine that directs patients’ own immune systems to fight their cancer.

Dogs, on the other hand, get cancer naturally, just as people do, and have intact immune systems.

“Genetically, you are a lot more like your dog than that mouse running around a cage in the lab,” said Nicola Mason, a veterinarian and immunologist who oversees the vaccine and several other canine trials at Penn’s School of Veterinary Medicine. “Where dogs really stand out is in the way they generate tumors and react to treatments, which is a lot like people."

The vaccine Flyer got, for example, is now in an early trial for people after it showed impressive results in a previous Penn dog study. The company sponsor hopes to develop it for children and adolescents, who are more likely than adults to get osteosarcoma.

Nicola Mason, associate professor of medicine and pathobiology at Penn's School of Veterinary Medicine, leads clinical trials of novel immunotherapies developed to treat dogs with cancer. Some could also benefit humans fighting the disease.  The dog and human versions of that cancer involve many of the same genes and are biologically similar. “What we learn in one species can be applied to the other,” said Robert Petit, chief scientific officer of Advaxis, the company testing the vaccine in people.

Across the country, medical and veterinary schools are partnering to find new treatments for malignancies from lymphoma and melanoma to brain and bladder cancer. The National Cancer Institute is overseeing canine trials at almost two dozen academic vet schools, and animal-health foundations are stepping up their support.

Immunotherapy is the latest rage in veterinary medicine, just as in human cancer treatments. Researchers hope studies in dogs can help explain why some people benefit from the approach and others don’t. Amy LeBlanc, director of NCI’s Comparative Oncology Program, said dog data can give drug companies “the necessary reassurance” to move forward with a promising treatment.

Not everyone is sold on the idea that pets will be that helpful for testing treatments in people. Many experiments are in the early stages. Laurence Baker, an oncologist at the University of Michigan who specializes in bone cancer, said that while he is “agnostic” about using pets for research, “in this area, as in too many areas of research, there is a lot more hype than success."

Proponents of comparative oncology dispute that, saying the similarities of some cancers suggest benefits for both species. Cancer is the biggest health threat facing dogs, killing half of those 10 and older. “They are patients, not lab animals,” said Mason, whose office is filled with photos of dogs she has treated, including Aspen, a greyhound wearing bunny ears, and Bogie, a Great Dane.

Most cancer drugs for dogs were developed first for humans. Take Harley, a striking 4-year-old black boxer with aggressive leukemia. He recently came to Penn for a treatment called CAR-T-cell therapy, which has shown some promising results in trials for people with blood cancers. The immunotherapy procedure for dogs is similar to the human one: T-cells, a key component of the immune system, are extracted, genetically modified in the lab to bolster their cancer-killing abilities, increased in number and then reinfused.

Mason began working on the treatment for dogs when she was a postdoctoral fellow in the lab of Carl June, a prominent researcher at Penn’s Perelman School of Medicine and a CAR T-cell pioneer. She consults with him frequently.

Owners of dogs in the Penn Vet trials get much of the care free, including treatments and follow-up visits. But there can be related expenses. In the osteosarcoma trial, owners are required to pay for the amputation and chemo.

If these canine treatments end up being sold outside clinical trials, they could carry hefty price tags. The human version of CAR-T-cell therapy, for example, which is still in clinical trials, could cost hundreds of thousands of dollars once it hits the market. Scientists hope more progress will lower the cost for people and dogs alike.

The notion of using canines as a model for human cancers goes back decades. When veterinary oncologist Stephen Withrow was an intern at the Animal Medical Center in New York in the 1970s, he attended rounds at nearby Memorial Sloan Kettering Cancer Center and realized that animal and human medicine could help each other. “It opened my eyes,” he said.

Children with osteosarcoma have benefited from that insight. Withrow, who went on to found Flint Animal Cancer Center at Colorado State University, developed a surgical technique that allowed dogs with bone cancer to avoid amputation. He then collaborated with an orthopedic surgeon to adapt the limb-sparing technique for children.

In the 1990s, when an 11-year-old Colorado girl named Emily Brown was diagnosed with an especially complicated case of osteosarcoma, her doctors asked Withrow if there were any new canine treatments. He suggested an experimental therapy that Brown, now 30, credits with saving her life.

The sequencing of the dog genome in 2005 increased interest in comparative studies. “If the human genome is a deck of cards and you shuffle it, you end up with a rabbit — and shuffle it again, and you end up with dogs,” said geneticist Matthew Breen, whose lab at North Carolina State University’s veterinary school was involved in the sequencing project.

Marie Cary, who lives near Myrtle Beach, S.C., turned to Breen’s school a few years ago when her retriever, Gracie, developed a tumor on her upper jaw. After the cancer failed to respond to chemo, veterinary oncologists recommended an experimental treatment in which tiny particles were injected into the tumor with a light-sensitive compound called psoralen. X-rays then were used to target the particles, which responded by emitting ultraviolet light. That activated the compound and caused it to interfere with the tumor cells’ DNA and incite an immune response.

After a few rounds, the tumor disappeared; Gracie is now 10. The vet school is working with Duke Cancer Institute and the sponsoring company, which hopes to move the therapy into human trials.

Some comparative-oncology studies use cats for cancers such as ORAL MALIGNANCIES and BREAST CANCER, which have similarities to the human versions. But cats are used less frequently in studies than dogs, researchers say, because less is known about their tumors and they tend to get more stressed out interacting with people.

Osteosarcoma is diagnosed in about 10,000 dogs a year in this country, and researchers suspect that most die because the disease has already spread to their lungs. About 800 people also are diagnosed here annually, many of them children and young adults. Almost three-quarters are treated successfully with chemo; the rest die of advanced disease.

At Penn Vet, the vaccine trial in which Flyer was enrolled sprang from a collaboration between Mason and Yvonne Paterson, a microbiologist in the university’s medical school who survived breast cancer. The vaccine, which Peterson developed, uses genetically modified listeria bacteria to target cancers that are positive for a protein found in osteosarcoma, as well as in breast, gastric and other cancers. The bacteria, weakened so as not to cause illness, is designed to stimulate the immune system to recognize and eliminate any cancer cells remaining after chemo.

Mason launched the first trial in 2012 with 18 dogs. All got the standard treatment — amputation followed by chemo — then three vaccine doses. The first participant was Sasha, an American bulldog. She survived 738-days, compared with a median 423-days for dogs that had been treated in the past with amputation and chemo alone.

“I was a little worried about the possible side effects, so I put her in the ICU and sat with her for three days,” Mason said. “But it was anticlimactic. She did great."

Many of the dogs did even better than Sasha, with median survival of 956 days. The vaccine now will be tested in a nationwide trial involving dozens of dogs.

In the meantime, Advaxis got the go-ahead from federal regulators to start an early-stage human trial with adults. Mason’s dog data was especially important in allaying concerns about possible heart damage. The company wants to launch a study next year for children with the aim of improving their treatment response and reducing relapse.

A few weeks after Flyer got a clean bill of health, Harley arrived for the CAR T-cell therapy for his leukemia. Mason had treated four dogs with lymphoma, but the first three had advanced disease and died quickly. The fourth survived for seven months.

To try for better results, Mason’s team changed the way it modified the T-cells, bringing its procedures more in line with the techniques used for people.

Harley’s T-cells had been withdrawn during an earlier visit, genetically altered and then multiplied. Now it was time for the 20-minute infusion. Erika Murphy of Franklinville, N.J., a teacher and mother of a young son, wept as she talked about the dog’s illness. “He’s our first boy,” she said.

Mason sat with him on a plaid blanket on the floor of a treatment room. Maloney Huss administered the altered T-cells via an intravenous catheter. Harley panted heavily but was calm, watching as a collie and other dogs strolled by.

The following week, he was back for tests. “He looks great,” Mason said, but the signs were mixed. “The cancer is coming back, but we are also seeing the T-cells starting to expand. Will they be able to start knocking back his cancer? We are all on tenterhooks to see."

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ESC POSITION PAPER ON ANTICANCER TREATMENTS AND CARDIOVASCULAR TOXICITY

The European Society of Cardiology (ESC) has recently published in the European Heart Journal a Position Paper in which cardiovascular complications of anticancer therapy are divided into nine main categories and further discussed in term of pathophysiology and clinical presentation, diagnostic and therapeutic management:

  • myocardial dysfunction and heart failure
  • coronary artery disease
  • valvular disease
  • arrhythmias, especially those induced by QT-prolonging drugs
  • arterial hypertension
  • thromboembolic disease
  • peripheral vascular disease and stroke
  • pulmonary hypertension
  • pericardial complications

The document was developed under the auspices of the ESC Committee for Practice Guidelines by a Task Force chaired by Jose Zamorano and Patrizio Lancelotti and including representatives of the International CardioOncology Society (ICOS). The document covers all aspects of cardiovascular toxicity in the context of anticancer treatment, providing expert opinion for management (given the paucity of randomised evidence) and summarising the most important recommendations.

Advances in anticancer treatment have led to improved survival of patients with cancer, but have also increased morbidity and mortality due to treatment side effects. Cardiovascular diseases are one of the most frequent of these side effects, and there is a growing concern that they may lead to premature morbidity and death among cancer survivors. This may be the result of cardiotoxicity, which involves direct effects of the cancer treatment on heart function and structure, or may be due to accelerated development of cardiovascular disease, especially in the presence of traditional cardiovascular risk factors, the authors wrote in an introductory part of the document.

Many aspects of both radiation- and anticancer drug­induced cardiovascular disease are still to be fully elucidated. The authors underlined that the complex issue of cardiovascular disease as a consequence of previous anticancer treatment requires the creation of multidisciplinary teams involving specialists in cardiology, oncology and other related fields. However, the extent of care and the interaction between the disciplines involved has not yet been defined.

The authors also wrote that a complexity of the clinical questions to be addressed by cardio-oncologists will require definition of a curriculum describing the necessary knowledge and skills to deliver optimal care and the hospital setting in which these experts will be active.

They emphasised that cardio-oncology teams should also be involved in the long-term surveillance of cancer survivors with a potential for late-onset cardiovascular complications and in the development of potential new treatments that may have cardiotoxic effects, as well as in the evaluation of cardiac events related to such drugs.

The document reviews the different steps in cardiovascular monitoring and decision-making before, during and after anticancer treatment with potential cardiovascular side effects. Although this document is not a formal clinical practice guideline, it aims to assist professionals involved in the treatment of patients with cancer and survivors by providing an expert consensus regarding current standards in aspects of care related to cardiovascular toxicity induced by anticancer treatment. The paper provides a valuable resource not only to professionals involved in cancer care, but to all healthcare professionals exposed to cardiovascular diseases.

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EXPERTS TACKLE COMBINED THERAPIES IN PROSTATE CANCER

By Joel Vega

Systemic treatments and optimizing various forms of therapies in high-risk and metastatic forms of PROSTATE CANCER were examined at the first-day plenary session of the 8th European Meeting on Urological Cancers (EMUC16) in Milan, Italy.

With around 1,300 registered participants, EMUC’s eight edition examines the whole range of issues in onco-urological diseases from the perspectives of medical oncology, urology, radiation oncology, pathology and radiology.

“We aim not only to provide a unique platform for all the specialties but also foster education through a multi-disciplinary approach in collaboration with our colleagues from ESMO, ESTRO and affiliated partners," said EAU Adjunct Secretary General for Education Hein van Poppel during the opening session where he was joined by Thomas Powles (ESMO), Peter Hoskin (ESTRO), Raymond Owen (ESUR) and Rodolfo Montironi (ESUP).

With the opening session on prostate cancer chaired by Manfred Wirth (DE), Susanne OSanto (NL) and Peter Hoskin (GB), urologist R. Jeffrey Karnes (USA) discussed the optimal use of adjuvant radiation therapy following radical prostatectomy, particularly on current efforts to integrate clinical and genomic features of locally advanced, high-risk disease. He looked into post-operative radiation therapy timing, the findings regarding genomic classifiers in the Decipher study, and various translational studies that examined adjuvant radiation therapy (aRT) versus salvage RT (sRT).

Among the issues that Karnes raised in his presentation are the benefits of sRT for men with low genomic scores (GC), and whether there was a statistically significant decrease in metastases development in men with higher GC who received aRT. He also looked into the issue whether integration of GC can provide additional insights.

“At present we have hypothesis-generating genomic studies (2015-2016) on post-operative RT. Modeling studies indicate cost-effectiveness, and the next step is the application to randomized trials,” said Karnes. He also expected the field to move toward a more personalized approach.

“We hope to see prognostic signatures to better identify ‘aggressive' disease and risk-stratify such as in the Decipher study,” he said.

Providing the medical oncology perspective, Karim Fizazi (FR) discussed the role of adjuvant systemic approaches following curative treatment, noting that patients with high-risk disease should have a local treatment. He also posed the query: “The worse the prognosis, the higher the benefit from docetaxel?” to which he later gave an affirmative answer.

In his closing remarks, Fizazi said that chemotherapy provides benefit in high-risk localized prostate cancer. “Docetaxel improves recurrence-free survival (RFS) such as shown in the GETUG 12, RTOG 0521 and STAMPEDE trials,” he said. However, he noted that docetaxel’s effect on overall survival is still unknown but with the prospect that new insights can be learned in the next few years.

Meanwhile, urologist Karim Touijer (USA) discussed what can be the best multi-modal approach for node-positive disease as he noted that there is no clear consensus in the management of node-positive disease.

“The choice of therapy is driven by the physician’s preference or institutional standards and these are observation and treatment after biochemical recurrence, adjuvant androgen deprivation therapy (ADT) and a combination of adjuvant ADT plus External Beam Radiation Therapy (EBRT). “The benefit of immediate adjuvant treatment over observation is unknown," he added.

In rounding up his presentation, Touijer stressed that node-positive disease is a heterogeneous group and that maximizing local control with radiation therapy in combination with ADT improves survival.

“Multimodality therapy with radiation and ADT after surgery is of greatest value in patients with the worst pathologic features,” said Touijer. Regarding prospects in the future, he said that molecular imaging could refocus the debate. “Furthermore we need better staging and image-guided therapies,” he said.

Radiation oncologist Gert De Meerleer (BE) presented current developments in salvage radiotherapy for locally recurrent disease, probing into issues such as when and how to deliver the treatment. “Early salvage equals adjuvant radiotherapy,” said De Meerleer, as he noted that adjuvant hormonal treatment improves biochemical relapse free survival (bRFS), distant metastases free survival (DMFS) overall survival, cancer-specific survival (CSS).

Metastatic prostate cancer

In the follow-up session which tackled metastatic prostate cancer, urologist Anders Bjartell (SE) took up oligo and polymetastatic prostate cancer. “Oligo and polymetastatic prostate cancers are more than two distinct entities,” said Bjartell as he underscored that there is a need for more “sensitive and quantitative imaging tools for stratification."

“Location of metastases may be more important than number of lesions with regards prognosis and treatment,” said Bjartell.

Radiation oncologist Malcolm Mason (GB) gave an update on using chemotherapy in hormone-sensitive prostate cancer and said current guidelines recommend castration combined with chemotherapy to patients whose first presentation is M1 disease and who are fit enough for chemotherapy.

He, however, cautioned that systemic treatment such as docetaxel is “not a trivial treatment” and that chemotherapy-related deaths do occur. “We need greater biological understanding of who benefits,” Mason said.

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HAVE A HAPPY, HEALTHY HOLIDAY!  UNTI. 2017....

And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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