Intralesional Therapies Help Bridge the Gap Between Improved Results and Less Toxicity

CURE, Immunotherapy Special Issue 2021,

First immunotherapy, intralesional therapy, is making a comeback and producing durable remissions for a subgroup of patients with cancer.

In 2011, when Harry Clark was 60 years old, he noticed a mole on his right shin. Even though he grew up under the hot Tucson, Arizona, sun and jokes that he lost his dark bronze tan every November, Clark didn’t think much about the dime-sized, dark red spot — and he’d never seen a dermatologist.

“It wasn’t causing any discomfort and it didn’t grow or change shape,” he says. “When I asked my primary care doctor to take a look, he said it was nothing to worry about.” Two years later, his new primary care provider saw the mole and immediately sent him for a biopsy.

A talented musician, Clark soon discovered he had melanoma, a disease that strikes over 100,000 Americans each year. Surgeons cut out the diseased skin on his shin. But his stage of melanoma required additional treatment. Clark endured 32 radiation treatments. Then he went through isolated limb infusion, in which doctors isolate the limb from the rest of the body with a tourniquet and then flood the area with heated blood and high-dose chemotherapy. “The treatment is so toxic, you have to be hospitalized,” Clark says.

Throughout Clark’s treatment for advanced stage 3 melanoma, new lesions continued forming. Clark’s wife, fellow musician Sanda Schuldmann, thought there might be a solution. A fan of the pianist Martha Argerich, Schuldmann knew that Argerich had received a diagnosis of stage 4 melanoma that had spread to her lungs decades before. She also knew that doctors at John Wayne Cancer Institute in Santa Monica, California, had treated Argerich with something called intralesional therapy.

With intralesional therapies, doctors administer treatment by needle injection directly to the tumor to jump-start the immune system and possibly obliterate cancerous tumors throughout the body. The late Dr. Donald Morton was among the first to repurpose the anti-tuberculosis drug bacillus Calmette-Guerin (BCG) as a first-line intralesional therapy for late-stage melanoma, publishing astonishing results in Annals of Surgery in 1974. In the study of 151 patients, Morton and his colleagues found that directly injecting BCG into metastatic melanoma lesions limited to the skin produced a 90% regression of injected lesions and a 17% regression of lesions that were left untouched. What’s more, one-quarter of these patients remained disease free for one to six years. Since BCG is still not Food and Drug Administration (FDA)-approved for the treatment of melanoma, it can be difficult to find physicians who are familiar with using it in this way.

Schuldmann reached out to John Wayne Cancer Institute, where she connected with Dr. Mark Faries, who is now a professor of surgery and co-director of the melanoma program at Cedars-Sinai The Angeles Clinic and Research Institute. Faries, who trained under Morton at the National Institutes of Health, agreed to review Clark’s medical records. Within days, Clark learned he was a candidate for BCG intralesional therapy and began traveling to California weekly to receive the experimental treatments. After 15 to 20 BCG injections, Clark’s lesions were gone.

Once considered an incurable disease in its advanced form, melanoma has emerged as one of the cancers most responsive to immunotherapy. Immune checkpoint inhibitors have dramatically improved outcomes for patients with late-stage melanoma, with more than half of patients on combination Yervoy (ipilimumab)/Opdivo (nivolumab) still alive years after treatment. Unfortunately, the remaining half don’t respond to treatment, and some experience debilitating side effects that force them to discontinue immunotherapy.

“Intralesional therapies can help bridge this gap by modifying the tumor microenvironment in such a way that the immune system can recognize it as foreign and attack, but without the toxicities of systemic treatment,” says Dr. Lynn Schuchter, chief of the division of hematology/oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia. The hope is that injecting these therapies at the tumor site will train the immune system to identify cancerous cells and launch a systemic and sustainable attack. For patients like Clark with late-stage disease that hasn’t metastasized to distant sites, intralesional therapy can produce durable remission.

INTRALESIONAL THERAPY EXPLAINED

Intralesional therapy is the oldest form of immunotherapy and dates back to the 1890s. In its early stages, intralesional therapy was made with neutralized, non-live bacteria and other stimulatory proteins without a clear understanding of the immune system. “More recently, we’ve learned why the immune system shuts down closer to the level of the tumor, and now we have drugs that can make the tumor visible to the immune system,” says Dr. Genevieve Boland, surgical director of the therapeutic intralesional program at Massachusetts General Hospital in Boston.

The goal of intralesional therapies is to attract the body’s killer T cells and draw them toward the tumor. In fact, one of the first approved immunotherapies for melanoma was the inflammatory cytokine interleukin-2 (IL-2) because cytokines attract T cells to tumors. Unfortunately, agents like IL-2 and BCG fell from favor because of systemic side effects and inconsistent results. Patients experienced significant toxicities ranging from anaphylaxis to changes in blood pressure and heart rate with IL-2.

“We’ve now learned that the immune system doesn’t work the same way that other drugs work,” Faries says. “There’s a sweet spot for how much stimulation you need to induce the desired effect.” And you can get there by using the tumor as a weapon against itself.

The idea behind intralesional therapy is to activate both innate and adaptive immunity to transform the patient’s tumor into a personalized vaccine. The innate immune system is ready to roll when faced with a threat. It automatically kicks in when a person cuts a finger, develops strep throat or needs to fight off the common cold. Adaptive immune cells need to be trained and activated to fight disease.

“These adaptive immune cells help create the right microenvironment for the fighter T cells to come in and do their job,” Boland says. And since doctors inject therapies directly into the tumor, they can deliver drugs safely and at a much higher dose than systemic drugs like checkpoint inhibitors.

USING VIRUSES TO ACTIVATE THE IMMUNE SYSTEM

Denis McGlynn of Camden-Wyoming, Delaware, received his first melanoma diagnosis in 2011 at 65 years of age. After multiple surgeries to treat the aggressive skin cancer, the married father of two and grandfather of five had his first experience with immunotherapy in June 2019. Within days of completing 13 months on Opdivo, McGlynn experienced debilitating side effects.

“I was lying on my back for five days because every joint in my body ached,” recalls McGlynn. The steroid medication prednisone instantly quieted his pain temporarily. Today, he still takes 6 milligrams of prednisone daily for the autoimmune effects.

To make matters more complicated, McGlynn continued to develop cancerous lesions on his scalp. That’s when his doctor suggested he visit Penn Medicine for intralesional treatments with an agent called T-VEC (talimogene laherparepvec). “I had multiple lesions, and the T-VEC injections took only five or six seconds each,” McGlynn says. “When I came back two weeks later, all of the lesions were either healing or gone.”

T-VEC is a genetically engineered herpes virus that obtained FDA approval in 2015 to treat patients with stage 3 or stage 4 melanoma who have injectable lesions but who are not eligible for surgery. Intralesional T-VEC works in these cases because it’s a modified virus, and research suggests viruses are among the best agents to reactivate a tumor’s microenvironment.

“The immune booster is attached to the virus and the virus has the ability to enter cells. When you inject this conjugate of the herpes virus with the immune booster into a melanoma nodule, it’s like raising a red flag and saying, ‘hey, immune system, here I am — attack me,’” Schuchter says.

Called an “oncolytic virus” because of its ability to selectively target, infect and annihilate tumor cells, T-VEC essentially trains the immune system to identify and attack the cancer not only in the injected tumor but also all tumors susceptible to the immune response — and in some cases, it produces complete responses.

“These oncolytic viruses rupture the tumor and kill cancerous cells while simultaneously stimulating the immune system,” Boland says. “We can create this superactive immune response locally, at the site of the tumor, while limiting or even eliminating the toxicities associated with traditional immunotherapy.”

In McGlynn’s case, the treatment was wildly successful. He hasn’t seen a lesion reappear since his last treatment in October 2020. Researchers are investigating other potential targets for melanoma, including other viral vectors, such as coxsackieviruses, HF-10, adenovirus, reovirus, echovirus and Newcastle disease virus. They’re also exploring another class of drugs to boost “innate immunity” — the immune system’s first responder cells that trigger T cells to kill tumors. Like viruses, these therapies activate the warning signs required for the immune system to launch an effective attack against a foreign invader. “Ideally, this sets off a strong reaction within the body that can turn an immunologically ‘cold’ tumor into a ‘hot’ one,” Boland says.

No matter which agents doctors choose, side effects of intralesional therapies tend to be minimal, particularly compared with systemic treatments. The most common complaints relate to soreness at the injection site and mild fatigue. However, a small subgroup of patients may develop inflammatory syndromes like those doctors see with checkpoint inhibitor therapy.

INTRALESIONAL THERAPY BEYOND THE SKIN

Down the line, combination treatment with intralesional therapy and checkpoint inhibitors may even play a role in the treatment of complicated tumors, such as stomach and pancreatic cancer. “The tumor microenvironment of pancreatic cancer has a lot of fibrous tissue, so the local tumor environment acts like a shield hiding the cancer from the immune system,” Schuchter says. “Using ultrasound guidance and other techniques, doctors can inject therapy directly into the tumor to help the immune system recognize cancerous cells and destroy them.”

Unfortunately, scientists don’t know yet who is most likely to respond to treatment. They don’t know whether it’s best to use intralesional therapies as a first-line approach or a last-ditch effort.

“Even though we inject T-VEC directly into tumors, it’s still a weakened form of the herpesvirus, and that makes it potentially dangerous,” Schuchter says. “Patients also have to cover the lesions for a week, and staff have to implement a variety of safe handling practices.”

Some clinics reserve a specific room for intralesional therapies and perform the procedure only at the end of the day. Others have strict preparation and cleaning requirements. And all intralesional therapies require consistent refrigeration. This level of preparation, time, training and logistics can be challenging or even impossible for community clinics.

“It’s important not to overhype intralesional therapy since it’s relevant for only a small subset of patients,” Schuchter says. But when it works — and sometimes it does work — patients reclaim their lives and enjoy decades-long survival. Innovations to this type of therapy with newer drugs are entering clinical trials.

“My one wish is that more people knew that intralesional therapy is an option,” Clark says. He is so indebted to BCG — he credits the drug with saving his life — that he partnered with a musicologist friend from his Peabody Institute days to develop a musical composition using notes B, C and G for Faries. “It’s probably the first fugue for a drug,” he says. Now that’s something to sing about.

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