A patient may walk into the emergency room with a complaint of shortness of breath and dry cough. It could be one of many problems, but these are two main signs of interstitial lung disease. Also referred to as ILD or pneumonitis, the disease is a lung condition that affects as many as 100,000 people in the United States, according to Cedars-Sinai in Los Angeles. The general mechanism of ILD is inflammation, yet in the majority of these cases, it is not clear what causes the inflammation in the first place, whereas in others, it can be due to specific types of infections. In a time of new cancer therapeutics, however, one particular reason is immunotherapy. Patients with cancer who are treated with checkpoint inhibitors or immunotherapy, along with other treatments, run the risk of developing ILD as a side effect. Because of this, it is of the utmost importance that they be aware of the symptoms and side effects.

In this issue of CURE®, we speak with three experts on the development of ILD as a side effect of immunotherapy. Regarding this relatively new concept (reported cases of lung distress associated with immunotherapy started coming in around 2017), one expert noted that 2.5% or 3% of patients on immunotherapy develop ILD, and that there is still a lot to learn about the topic. She also spoke on the importance of catching the disease early in order to stop its progression. Another expert said it’s not a huge surprise that ILD is a side effect since it tends to be a risk to those with autoimmune disease, the common denominator being an overactive immune system that can cause inflammation in normal tissue.

On the topic of the awareness of side effects, you’ll find an article detailing what to keep an eye out for when going through cancer treatment, as well as the best steps to take. Some of the therapies used for this situation are also discussed.

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Patients with cancer who are treated with checkpoint inhibitors or immunotherapy, along with other treatments, run the risk of developing ILD as a side effect.

Side Effects of Immunotherapy Now Include Interstitial Lung Disease

From immune checkpoint inhibitors and T-cell therapies to cancer vaccines, immunotherapy is a strong pillar in the treatment of cancer. And thanks to ongoing research and clinical trials, it seems that there are always new immunotherapies emerging — all with the goal of eliminating or reducing cancer from the body. In this special issue of CURE®, we dive into many of the latest updates on some of these treatments as well as new and upcoming regimens that are making differences in the lives of patients with cancer.

BiTE therapy, for example, is an emerging treatment in this space that wages a two-pronged attack on tumors via bispecific antibodies. For our feature on BiTE therapy, we spoke with a patient who received a diagnosis of high-risk multiple myeloma. After he underwent years of chemotherapy and Venclexta (venetoclax), his cancer returned. It was then that he qualified for a clinical trial of teclistamab, an investigational bispecific antibody drug in the field. His cancer load dropped 99% after one dose.

As new therapies emerge, old ones are also making a comeback, one of which is intralesional therapy. Considered the first immunotherapy, intralesional therapy teaches the immune system to kill cancerous tumors throughout the body. We spoke with one patient with melanoma who found this treatment option through music. His wife, who was a fan of pianist Martha Argerich, knew that the musician had received a diagnosis of stage 4 melanoma that spread to her lungs, and had undergone intralesional therapy at John Wayne Cancer Institute in Santa Monica, California. After reaching out to the same cancer center, the patient was treated with the therapy and now credits it with saving his life. He was even inspired to create a musical composition. Both patient experiences show how big a role immunotherapy can play in treating cancer.

Although immunotherapy can greatly affect patients’ lives, one of the most common worries involves finances. In this issue, we also speak with an expert about tips for how to approach costs of treatments — even if you’ve been denied coverage by your insurance. You’ll also see an article on the side effects of immunotherapy, symptoms to look out for and the steps to take if you start to develop them. Regarding the future of immunotherapy, we’ve also spoken with experts on the newest updates in T cells, cancer vaccines and combination therapies.

From the Chairman

Thanks to ongoing research and clinical trials, it seems that there are always new immunotherapies emerging.

The Impact of Immunotherapy

Although rates of head and neck cancer have risen, in part because of the human papillomavirus (HPV), emerging therapies such as targeted agents and immunotherapies are paving the way for future treatment of the disease, according to Dr. Michael Moore.

“I would say (immunotherapy) is probably one of the more exciting parts of what we’ve learned about head and neck cancer in recent years,” he told CURE® as a part of its “Speaking Out” video series.

On behalf of the Head and Neck Cancer Alliance, CURE® spoke with Moore, associate professor of otolaryngology-head and neck surgery and chief of head and neck surgery at Indiana University School of Medicine in Indianapolis, about targeted therapies, immunotherapy and how clinical trials are leading the way for future treatments.

How have genomics and targeted therapies played a role in head and neck cancer treatment?

Well, I would say it’s an emerging role. And it’s not used as commonly in head-neck cancer as it is in some other areas. So molecular testing or targeted therapies essentially are looking at a very specific part of the tumor to see if we can develop a specific drug that will target just that; (the goal is to) weaken the cancer’s defense — that is one way to say it — and try to very specifically treat that cancer in a way that will give us the best chance of getting rid of it and potentially try to limit the side effects related to the treatments. This has become a little bit more common now that the ability to analyze these tumors has become more widely available across the country. But still, the majority of these types of treatment approaches will be in the context of a clinical trial.

Do we have any currently approved targeted therapies for head and neck cancer?

That’s a great question. I think these are kind of different and are emerging all the time. There are ones that are focused on very specific mutations, such as what’s called the BRAF mutation, which is one that can be present in melanoma or certain aggressive cancers, such as thyroid cancer. And other ones will target things like tyrosine kinase inhibitors that have a more focused route to try to combat these tumors. And then there are ones that will be discussed a little later, such as immuno-oncology drugs that focus on the program cell death ligand and the receptor to try to turn the body’s immune system back on. Another example is what’s called Erbitux (cetuximab), which is focusing on a specific receptor on cancer cells, really trying to exploit this particular difference in cancer cells compared with normal tissue to try to give the best chance of getting rid of the tumor, but minimizing the side effects of the treatment.

What role has immunotherapy had in head and neck cancer treatment?

Cancer has a way of almost turning off the local immune system. It blocks many of the local immune responses to it. Normally, the body would say, “Yeah, that’s not part of our normal tissue, we want to get rid of it.” And some cancers have a way of blocking that. These immunotherapies have a way of almost inhibiting that blockage, if you will, or turning the immune system back on and allowing your own body’s immune system to fight these tumors. These can be incredibly effective. The challenge is if they’re only effective in a small minority of cancers. And so, when they do work, they can work extremely well and can give really good and long-lasting results. But in a high percentage of patients, the responses are much more modest or (patients) may not even respond at all.

Can you discuss the currently available immunotherapies for head and neck cancer?

There are two. Opdivo (nivolumab) is one that can be used in patients who have not responded or progressed despite standard therapy, including recent treatment with chemotherapy, including cisplatin. And then Keytruda (pembrolizumab) is another similar amino therapy that can be used and has actually achieved approval for use in the primary setting. When cancer comes back in an area that can’t be treated with either definitive surgery or definitive radiation therapy, you can use that as a next avenue for treatment. These are the two (Food and Drug Administration)-approved drugs that are out there. They also have ongoing studies where they’re being combined with other standard-of- care, primary treatments for head and neck cancer. I think in the next five to 10 years, they’ll likely be integrated much more on the front end of cancer therapy, rather than just offering them to those who don’t have other treatment options.

How do clinical trials help to advance these therapies, and why should patients consider joining one?

These are really what allows us to make our cancer treatment better. We constantly are. It’s not just going out and experimenting on people but, rather, we’re comparing these treatments to see how we can improve on the current standard approach to therapy. If you were to look back 50 to 60 years ago, all we had were big, morbid surgeries that people were put through and possibly adding radiation therapy. And then we added cisplatin, which is a drug that can be effective in enhancing the effects of radiation therapy. Now, as we add these other treatments, such as immunotherapy and other targeted therapies, the only way we know if they have any advantage over what we have to offer, currently, is to compare them in a clinical trial.

And with these clinical trials, those who have designed them have been very thoughtful in trying to do so in a way that compares them and then looks to see: Does that give us a benefit in getting rid of the cancer or curing the cancer, or at a minimum, slowing it down or giving a longer life? And/or does it give better quality of life or reduce the level of side effects? That’s what many of these clinical trials are. Some are adding new agents to see if those work better than other ones. For example, in the HPV-related cancer, some of the clinical trials are saying these respond fairly well to treatment. Can we actually back off on the severity of treatment, give them just as good of a cancer cure but (with) fewer long-term side effects? I think they’re critical as the only way we’re going to figure out how best to manage these types of cancers.

Speaking Out

On behalf of the Head and Neck Cancer Alliance, Dr. Michael Moore spoke with CURE® about emerging therapies that potentially offer exciting new options for the future.

‘On the Rise:’ Immunotherapy Options for Head and Neck Cancer

Although immunotherapy has become a major pillar in cancer, the current generation of T-cell therapies only benefits a minority of patients, one expert says.

“The problem is that we know only a minority of tumor types really benefit in a big way from these drugs,” said Dr. Mark Yarchoan, an assistant professor of medical oncology at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore. “And even within tumor types where they show a lot of activity, only a subset of patients respond, and fewer patients have really long-term remission.”

The use of T-cell therapy began in 1986 when Dr. Steven Rosenberg and colleagues at the surgery branch of the National Cancer Institute started using tumor infiltrating lymphocyte (TIL) therapy, in which doctors test lymphocytes (a type of T cell) to find out which one is best at recognizing tumor cells. From there, the selected lymphocytes are treated with substances that make them grow in numbers. “One of the limitations with (TIL) therapy is that you have to have TIL in your accessible tumor already,” said Dr. Lisa Butterfield, vice president of research and development at the Parker Institute for Cancer Immunotherapy, in an interview with CURE®. “CAR-T cell therapy is not specific to one patient’s tissue type, so that’s certainly a big strength.”

“I think the next frontier is, instead of broadly activating T cells, how do we activate T cells against specific cancer antigens?” Yarchoan said, adding that there is already exciting research underway for this. “Lots of different approaches are being explored, including cancer vaccines, new cellular therapies that utilize T cells that recognize tumor antigens, and bispecific antibodies that bring T cells into the tumor.”

When it comes to broadly activating T cells, there are also more check- point inhibitors coming — allowing immunotherapy to target alternative checkpoints outside of PD-1, PD-L1 and CTLA-4. There is also positive data circulating on how to keep cancer cells from turning off immune receptor TIGIT, which is present on some T cells and natural killer (NK) cells. Dr. Andrew Ewald is one of the faces behind some of this research.

Ewald, who is a professor and co-leader of the department of cell biology at Johns Hopkins University School of Medicine and professor of oncology and co-director at the Cancer Invasion and Metastasis Program at the Sidney Kimmel Comprehensive Cancer Center, discovered that using antibodies can stop cell receptors like TIGIT and KLRG-1 from manipulating NK cells: lymphocytes in the same family as T cells.

The research, which is in its final stages, found that the NK cells were the most abundant early responders to cancer cells arriving, and were particularly good at killing metastatic cancer cells. Ewald’s discovery would keep NK cells in their natural, cancer-killing state.

“It’s a way of keeping the good guys on your team and looking for, detecting and killing the cancer cells wherever they are in the body,” he said.

Butterfield also noted that new trials using CD19 and CD20 CAR T-cell therapy in hematologic malignancies are showing success. In CAR-T cell therapy, CD19, a protein expressed on most B cells, the white blood cells that make antibodies, is successfully targeted in cancers such as B-cell lymphomas. In this process, the therapy gets rid of both cancer cells and B cells. “In some patients, their cancer comes back but doesn’t express the CD19 protein on the surface anymore,” she said, noting that this could lead to resistance to CD19-directed CAR-T cell therapy. “To deal with that, the tumor can be targeted with CD20, which can often be expressed on the tumors as well as other normal B cells.”

Through using both CD19 and CD20 CAR-T cell therapy, the hope is that killer cells won’t become ineffective against tumor cells that downregulate one target, and that the therapy will “persist in patients as a one-time treatment that will keep an eye out for tumor cells that express CD19 and/or CD20, and not allow for resistance to one (or the other),” Butterfield said. 

A study being led by a researcher at UCLA, is currently evaluating this.

“I tell my patients to hang tight because there are better things around the corner,” Yarchoan concluded. “I show up to work every day feeling optimistic because our options are so much better than they were a year ago. And I’m really hopeful that they’ll be better in a year than they were today.”

One expert tells patients to ‘hang tight’ as immunotherapy options are getting better each year.

Immunotherapy Options Around the Bend

Earlier this year, BioNTech co-founder and chief medical officer Özlem Türeci stated that the messenger RNA (mRNA) technology used to develop two of the COVID-19 vaccines currently available in the United States could be used to treat another disease that affects millions of people around the world: cancer. The technology, which has been around since the 1990s but wasn’t widely used until now, carries instructions into the body to make proteins that prime it to attack a specific virus.

“The same principle can be applied to help a patient’s immune system to attack a tumor,” Dr. Julie Rosenberg, head of global clinical development at OncoPep, said in an interview with 

®. The biotechnology company focuses on developing targeted immunotherapies and is currently focusing on PVX-410, an investigational cancer vaccine being studied in patients with multiple myeloma and triple-negative breast cancer.

The discussion of mRNA’s potential to be used in the cancer field comes more than a decade after the Food and Drug Administration approved the first cancer vaccine: Provenge (sipuleucel-T). In 2010, it was approved for the treatment of advanced prostate cancer. Provenge is composed of a patient’s own stimulated dendritic cells — a type of immune cell responsible for “educating” the immune system on what to target. During the process, the dendritic cells are exposed to prostate antigens. Provenge is known for its toxicity, and Rosenberg noted that newer, less toxic vaccines that are in development are being studied in clinical trials. Side effects of Provenge can vary, depending on the patient, but include chills, fatigue, fever, headache, muscle pain and loss of appetite. “It’s basically a cellular therapy where you take people’s cells out of their arm, you send them to a factory, teach the cells how to recognize prostate cancer and give them back to patients,” said Dr. Thomas Marron, director of the early phase trials unit at The Tisch Cancer Institute and assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York. Overall, the goal of a cancer vaccine is to teach the body how to recognize something foreign.

Marron added that cancer vaccines can also help a patient’s immune system learn what to be on the lookout for when it comes to their specific cancer. “One of the reasons why patients might not respond to the new immunotherapies used to treat many cancers is their immune system might not have been taught how to recognize the cancer from the get-go,” he said. “A patient’s T cells, which are really the soldier cells of your immune system, may not have been trained to recognize mutated protein acts.”

Since Provenge, there has been only one other approved cancer vaccine. Talimogene laherparepvec is used to treat melanoma that has recurred after surgery. “(An) effective cancer vaccine must target tumor antigens that may have low immunogenicity in the tumor environment or that may mutate to evade the immune response,” Rosenberg added.

There have been plenty of clinical trials that have assessed cancer vaccines. “It’s really not that the vaccines haven’t worked. They just haven’t worked well enough,” said Dr. George Peoples, the founder and CEO of Cancer Insight and professor of surgery at the Uniformed Services University in Bethesda, Maryland. Peoples leads research and testing in immunotherapy developed under the military’s Cancer Vaccine Development Program. Of note, there are no other vaccines on the brink of approval, but there are many under investigation.

Marron is one of the researchers behind some of these cancer vaccines, one of which he described as “super personalized.” In an interview with CURE®, Marron used the example of a patient with lung cancer to explain his trial that was presented at the American Association for Cancer Research (AACR) annual meeting. Even when a tumor is surgically removed, these specific patients have a 50% or higher chance of the cancer eventually coming back, according to Marron.

“Our goal with the personalized vaccine was to create what we call an adjuvant therapy, which is a therapy that you get after surgery to further decrease the likelihood of cancer coming back,” he said.

In Marron’s recently completed phase 1 study that was presented at the AACR annual meeting, 15 patients were enrolled to test the safety and efficacy of an adjuvant personalized neoantigen peptide vaccine.

It was this study that computer scientist Marc Baum found while researching prophylactic immunotherapy, otherwise known as preventive cancer treatment. He previously received a diagnosis of bladder cancer at 54, and had just been declared cancer-free. “I did it for myself,” Baum said. “I’m (also) a scientist, so I wanted to help out and give back to the future (patients with cancer).”

Marron’s trial successfully administered the vaccine to 87% of patients over the course of 27 weeks, and results showed that the vaccine was well tolerated, with only half of the patient population experiencing mild side effects. Data also found that there was T-cell growth, as well as reactivity to synthetic neoantigens (proteins that form on cancer cells and help the immune system respond to and attack cancer cells).

“Personalized (cancer) vaccines were new news out there, and I just got lucky that there was one that fit,” Baum explained. Of note, Baum is still cancer free.

There are several variables behind the rigorous process of getting a new cancer vaccine approved, but the largest lies within the disease, according to Peoples. For diseases such as COVID-19, the vaccine is designed to generate a response against a bacteria or virus, but for cancer, the disease starts within the body’s normal cells, which makes it harder for the immune system to recognize it. In turn, Peoples says, a cancer vaccine has to train the immune system to recognize and destroy unhealthy cells. “That’s a really big ask for the immune system,” he said. “(Because of this,) cancer vaccines have trailed far behind infectious disease vaccines.”

Over the past two or three decades, most of the research behind cancer vaccines was driven by the goal to figure out a way to identify potential targets on cancer cells so the immune system could be trained to recognize the difference. More recently, checkpoint inhibitors proved successful at this. Because they allow T cells to regain their ability to recognize and kill cancer cells, their use in combination with T-cell therapies has been a huge step in the right direction. “Their underlying benefit has really closed the loop, if you will, on some of our understanding on cancer vaccines,” Peoples said. He describes the combination as a “natural marriage,” since bringing the two together keeps the T cells from being turned off, so to say, by the tumor, leading to an immune response. “We now prove the immune system has the capacity to recognize and destroy cancer,” he explained, noting that there’s an outpouring of clinical trials to explore these different combinations.

In response to this research, Peoples mentioned that the focus will switch to how to best use those vaccines in terms of testing in the right patient population. “That’s really the next wave for cancer vaccines,” he said.

Peoples broke it down using the example of a patient with breast cancer who has a 30% to 40% risk of recurrence. He says the recurrence could occur over the next two to three years. “(For) a clinical trial to test a vaccine, where we’re trying to see if we can reduce a recurrence rate from 30% or 40% down to 10% or 20%, and we have to wait three years to find out if we’ve done anything ... that’s a very long, very expensive, very laborious trial,” he noted.

This serves as a huge obstacle in getting cancer vaccines approved — especially considering the already rigorous clinical trial process. “A comprehensive vaccine development process can take eight or more years to complete,” Rosenberg explained.

However, Peoples emphasized, the most important thing to remember is that there is information out there to create an effective cancer vaccine. “Additionally, there are some new vaccine technologies coming down that are extremely exciting, some of which will come from this pandemic,” he said. “(And) we’ll continue to look for those rationale combinations that will be required to be able to overcome disease burdens in patients with metastatic disease.”

Research News and Updates

Even with newer technologies such as mRNA, experts predict it will be a few years before another cancer vaccine is approved.

‘The Next Wave’ in Cancer Vaccines

After Michael Herman received a diagnosis of high-risk multiple myeloma in 2013, he started a treatment journey that included several years of chemotherapy and the targeted drug Venclexta (venetoclax tablets), which is investigational for the disease and was designed for patients whose cancers have certain genetic abnormalities. The medicines worked well, but as is often the case with multiple myeloma, Herman’s cancer eventually returned.

In July 2019, Herman qualified for a clinical trial of teclistamab, an investigational drug that’s part of an emerging class of immunotherapy medicines known as bispecific antibodies. He traveled from his home in Galena, Maryland, to the University of Pennsylvania in Philadelphia to get the treatment: a weekly shot in the abdomen.

After just one dose of teclistamab, Herman’s cancer load dropped 99%. His disease is no longer detectable, and the study investigators have told him he can stay on the drug as long as it continues to be effective. In terms of side effects, Herman experiences some aches and pains, but says that it doesn’t affect him from getting around.

“When I was diagnosed, I was told my life expectancy was four years,” says Herman, 59, a retired corporate real estate manager. “This drug doubled that. It’s a wonderful thing.”

Teclistamab is one of several bispecific antibodies being developed to treat a range of cancers. Bispecific antibodies are designed to simultaneously bind two targets — a target on immune cells and another on tumor cells — pulling them together to unleash an immune attack against the cancerous cells. In the case of teclistamab, the two targets are an antigen called CD3 in the immune system’s T cells, and BCMA, which is an antigen that’s overexpressed in multiple myeloma.

Several other bispecific antibodies are under development to treat blood cancers and a wide range of solid tumor types, including cervical, gastric, brain and liver.

“The idea behind combination immune therapies, which include bispecific antibodies, is to find ways to better target the immune system from the get-go, to minimize the chance of resistance or improve the chance of getting a good response,” says Dr. Deborah Wong, an oncologist at UCLA.

The first, and so far only, bispecific antibody on the market, Blincyto (blinatumomab), is approved by the Food and Drug Administration (FDA) to treat some patients with acute lymphoblastic leukemia (ALL). The drug, referred to as a bispecific T-cell engager (also referred to as BiTE), has one arm that attaches to CD3 and a second that binds to the antigen CD19 on the surface of cancerous B cells.

In a trial of patients with relapsed or resistant B-cell precursor ALL, Blincyto increased the rate of complete remissions from 20% among patients on standard-of-care chemotherapy to 42%. In a pediatric study released in March 2021, 69% of children treated with Blincyto were still alive after nearly two years, and 93% showed no sign of disease. In a phase 2 study released in May 2021, there was a 95% response rate among patients with Philadelphia chromosome-positive ALL who received Blincyto plus the targeted drug Iclusig (ponatinib), showing the potential of treating patients without the need for chemotherapy, the researchers said.

Bispecific antibodies can cause side effects, including cytokine release syndrome, a severe inflammatory response marked by high fever, body aches and other symptoms. Although Herman experienced cytokine release after his first shot of teclistamab, he has had minimal side effects since then.

Bispecific antibodies could bring immunotherapy options to patients who aren’t eligible for treatments like CAR T cells, which are personalized therapies that entail removing immune cells from patients and engineering them to recognize and attack their cancer. Although these T-cell therapies can be lifesaving, they present challenges that could be avoided with bispecific antibodies, says Dr. Joshua Richter, assistant professor of medicine, hematology and medical oncology at the Icahn School of Medicine at Mount Sinai in New York.

“CAR-Ts are not off-the-shelf products, so they take time for manufacturing, whereas bispecifics are off the shelf,” Richter says. And even though there is a risk of side effects with bispecific antibodies, they are titratable, meaning they can be given in small doses to start and then in larger doses after the immune system is given a chance to adapt. “We are concerned about giving CAR-Ts to older people because some can get quite sick (from cytokine release),” Richter says. “It’s nice to have a more titratable alternative.”

Several bispecific antibodies aimed at multiple myeloma are in clinical trials now, some of which are showing early promise. In a phase 1 dose-ranging study of an intravenous formulation of teclistamab, for example, 58% of patients on the recommended dose for phase 2 trials showed a partial response and 30% had a complete response. Although 70% of participants experienced cytokine release, none had symptoms severe enough to prompt them to pull out of the trial. Other side effects included anemia, a drop in white blood cells and fatigue. A phase 2 study of the drug in multiple myeloma is ongoing and recruiting patients.

Another trial of a BCMA-CD3-targeted bispecific antibody, elranatamab, was paused in May because of cases of peripheral neuropathy reported by some patients. The drug’s developer, Pfizer, was asked to investigate the cases and report what it finds to the FDA. Patients in the trial who were benefiting from the drug were able to stay on it, but no new patients will be accepted until the investigation is complete.

There are other promising approaches to multiple myeloma in early-stage testing, Richter says, including a bispecific antibody called cevostamab, which targets CD3 and FcRH5, an antigen expressed on the surface of almost all multiple myeloma cells. Interim results from an ongoing phase 1 study that were reported in December showed an overall response rate of 53%. Responses were even seen in patients who had failed five previous treatments.

Another prospect in multiple myeloma is a bispecific antibody called GBR1342, which targets CD3 and CD38, an antigen implicated in the disease and other blood cancers. The drug, now in phase 1 testing, received orphan drug designation from the FDA in 2019, which could expedite its development path.

There are several bispecific antibodies in development to treat other blood cancers, including acute myeloid leukemia (AML). For example, a drug called flotetuzumab targets CD3 and CD123, a molecule called an interleukin-3 receptor that’s prevalent on malignant cells in AML. In a trial of the drug in patients who had relapsed after other therapies, 32% of participants achieved a response, and more than half of those were able to go on to receive stem cell transplants, which put them in remission.

The flotetuzumab trial results highlighted another potential advantage of bispecific antibodies, which is that they may offer patients a bridge to other treatments that could result in more durable remissions, such as stem cell transplants. The ALL treatment Blincyto has also been shown to offer some patients a good lead-in to stem cell transplants. In a trial comparing the drug to standard-of-care chemotherapy, the overall response rate to Blincyto was 44%, and 24% of the patients receiving the drug went on to have stem cell transplants.

Oncologists at The University of Texas MD Anderson Cancer Center in Houston are now testing Blincyto in patients with newly diagnosed ALL, and there are encouraging early results. Last year, researchers reported results from a small trial in which patients with ALL started with four cycles of chemotherapy and then were placed on maintenance treatments that included Blincyto. There was a 100% response rate, and 79% of patients stayed in remission for two years.

“Historically, we can cure about 40% to 50% of elderly patients with ALL, so if this response rate holds over time, it will be a tremendous improvement, essentially doubling survival rates,” said Dr. Marina Konopleva, a professor and physician-scientist in the department of leukemia and stem cell transplantation at MD Anderson.

Phil Briggs, who received a diagnosis of ALL in January 2018, was treated with Blincyto in the fall of 2020, after his cancer stopped responding to standard-of-care chemotherapy. He found the drug to be far more tolerable than chemotherapy, which had caused him to lose his appetite and drop more than 50 pounds, in addition to developing peripheral nerve damage. Aside from a slight skin irritation, “I felt fantastic,” says Briggs, 62, who is being treated at MD Anderson.

Briggs’ courses of Blincyto came in a portable pump, allowing him to receive the agent on an outpatient basis without having to go to the hospital. After four months on the drug, he was able to undergo a stem cell transplant and is now in remission. “I felt so much better that I was able to go straight from (Blincyto) to the stem cell trans- plant without any side effects,” says Briggs, who is now planning to go back to work as an insurance salesman.

Targeting solid tumors with immunotherapy has been difficult because they lack a single target for immune cells to latch on to, and the environment that surrounds them may not be conducible for immune cells to readily attack the cancer cells. The two-pronged design of bispecific antibodies could help overcome those hurdles.

Several bispecific antibodies being developed to treat solid tumors include one treatment group that targets an immune checkpoint like PD-L1 or CTLA-4, inhibiting it so the immune system can launch an attack.

For example, a bispecific antibody called FS118, which is now being tested in a phase 1 trial in solid tumors, has one treatment group that inhibits PD-L1 and another that blocks another immune checkpoint called LAG-3. Initial results from a trial released last year showed that patients who had been treated with PD-1 or PD-L1 blockers and became resistant to them had durable stabilization of their disease on FS118.

A bispecific antibody called XmAb20717 blocks PD-1 and CTLA-4 and is being tested in patients with a number of solid tumor types. The response rate in a trial reported last November was 19% and included a complete remission in one patient with melanoma. Partial responses were seen in patients with ovarian cancer, non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer.

Other bispecific antibodies in development to treat solid tumors target disease-promoting genetic mutations. One of these agents was recently approved by the FDA. Called Rybrevant (amivantamab-vmjw), it targets EGFR and MET in NSCLC with abnormalities in those genes. It is the first fully human, bispecific antibody approved in lung cancer. The approval was based on results from the phase 1 study, where the response rate to the drug was 40% in patients who had previously been treated with platinum chemotherapy, and 74% of patients saw their disease stabilize.

With so many bispecific antibodies in development across a range of cancer types, many patients could benefit from enrolling in clinical trials of these new therapies, says Wong. “Clinical trials are a good option to consider, especially if you’ve already been on standard therapies,” she says. “It may be that patients who responded well to their initial therapy and then developed resistance could be good candidates for bispecific antibodies.”

And because bispecifics target the immune system, they could improve the prognosis for many patients, Wong says: “The beauty of immunotherapy is that the immune system has a long memory, so there’s a potential for patients to have long-lasting responses to these drugs.”

Feature

BiTE therapy could lead to better ways to target the immune system, while minimizing the chance of resistance.

Bispecific Antibodies Wage a Two-Pronged Attack on Tumors

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 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.

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.

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

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

Advancements in the immune checkpoint inhibitor space have given some patients a new treatment option for cancer outside traditional chemotherapy or surgery options. Currently, there are seven inhibitors approved by the Food and Drug Administration: Yervoy (ipilimumab), Tecentriq (atezolizumab), Bavencio (avelumab), Libtayo (cemiplimab-rwlc), Imfinzi (durvalumab), Opdivo (nivolumab) and Keytruda (pembrolizumab). With these immunotherapies, however, come the possibility of side effects, and according to experts, it’s of the utmost importance that patients are aware of them.

Mild side effects can occur in 30% to 50% of patients, whereas serious side effects occur in less than 5%, according to the National Comprehensive Cancer Network. “Typically, I frame it such as that unlike chemotherapy, which is a poison to both good and bad cells, the immunotherapy is working to boost the patient’s own immune system to detect and get rid of the cancer cells,” said Bobbie Khan, a clinical nurse coordinator at Georgetown Lombardi Comprehensive Cancer Center and MedStar Georgetown University Hospital in Washington, D.C., on educating patients. Sometimes, Khan explained, the immune system is pushed into hyperdrive and begins to attack healthy organs and tissues. This often leads to inflammation in normal tissue including organs that can lead to the side effects and toxicities of immunotherapy.

Side effects can include encephalitis (brain inflammation), hormone gland problems (such as thyroid abnormalities), pneumonitis (lung inflammation), kidney inflammation, skin irritations or rashes, colitis (large bowel inflammation), hepatitis (liver inflammation), nerve problems, eye problems, and myocarditis or arrhythmia (heart problems). Symptoms of these side effects can show up as fever, yellowing of the skin, diarrhea, shortness of breath, worsening cough and muscle weakness, among others. Most of the side effects can be reversed by specific treatments.

“Very rarely, (immunotherapy) can cause very devastating side effects that are refractory to treatment, such as inflammation in the brain,” noted Dr. Aiwu Ruth He, an associate professor of medicine at Georgetown Lombardi Comprehensive Cancer Center and Georgetown University Medical Center. Although most side effects are sudden and resolved in a matter of days to weeks with or without treatment, toxicities can last for months or years.

According to Khan, who works on He’s team, the most important step for patients — besides recognizing their symptoms — is to call their oncologist on first notice. If patients don’t call right away, it can “create a cascade of effects in the body that are difficult to control once the dominoes start falling,” she emphasized. Another important point to recognize is that side effects can show up during or after immunotherapy and most often occur further into treatment.

Dr. Patrick Ott, clinical director of the Melanoma Center at Dana- Farber Cancer Institute and associate professor of medicine at Harvard Medical School in Boston, said he’s seen patients develop toxicities after being on immunotherapy for over a year. “It would be unusual if a patient starts immunotherapy and then after a couple of days or even after a week or two, they’re already having the toxicities,” he explained. “More commonly, they are on the treatment for four or five, six weeks, and then that’s when the onset of these toxicities occurs. Sometimes it could be many months into the treatment.”

Ott says side effects often affect only one system, but not always. “There’s no playbook,” he said.

Treating Side Effects and Toxicities of Immunotherapy

Treatment of side effects and toxicities often requires immunosuppressive drugs such as corticosteroids. Sometimes additional steroids or combination therapies are needed, depending on the severity of the side effect. In order to treat the side effects, patients have to take a pause from their immunotherapy treatment, which may cause worry about how that will affect outcomes. “When we give corticosteroids, it actually does not seem to impact the efficacy of the treatments,” Ott explained. “We have many patients who have their treatment stopped or held because of the toxicity, but the cancer actually still continues to respond, even off treatment.”

Ott noted that tinkering with doses has been shown to make a difference, particularly when checkpoint inhibitors are used in combination, such as Yervoy and Opdivo. For example, lowering the dose of Yervoy made the combination less toxic, particularly in lung cancer, where the doses commonly used in melanoma could not be tolerated. “Yervoy and its dosing made a pretty fundamental impact on the toxicity,” he said.

In instances where a side effect doesn’t respond to an immunosuppressant, He said she will often perform a biopsy to see if there are specific immune cells that a different immunosuppressant can target. “Normally, we don’t do it unless we are really puzzled about what has caused (the side effect) or it has not responded to the initial intervention,” He noted.

Knowledge

Experts urge patients to stop playing the wait-and-see game: There’s no ‘playbook’ for immunotherapy-related toxicities, and side effects can be managed if caught early.

Act Fast: Side Effects of Immunotherapy

Even with health insurance, immunotherapy — along with many other treatments — can be expensive for patients with cancer. In fact, many immunotherapies cost more than $100,000 a year per patient. Moreover, researchers recently estimated that the cost of oral prescription treatments for cancer will reach $25 billion by 2030.

However, there are steps patients can take to avoid a financial crisis as much as possible, according to Joanna Fawzy Morales, Esq., cancer rights attorney and CEO of Triage Cancer. CURE® recently spoke with Morales about these steps, as well as what other programs may help to alleviate costs.

CURE®: What are some options that patients can look into when it comes to paying for immunotherapy?

 Whenever a patient is considering (a) particular treatment, it’s incredibly important for them to talk with their health care team if they have concerns about what it’s going to cost them. What someone might pay for immunotherapy greatly depends on what type of insurance they have, and how adequate that insurance is. Many people choose their health insurance policy by the monthly premium without understanding the out-of-pocket maximum on a policy, and that’s actually one of the most important things to look at when buying a health insurance. We actually think that one of the primary ways that people can reduce financial toxicity is by having adequate health insurance where they’ve made a conscious choice to pick a plan with the lower out-of-pocket maximum. If you have an out-of-pocket maximum that’s $6,000 a year — some employer plans go up to $20,000 a year — that’s a huge burden for patients to pay out of pocket — especially for a higherpriced treatment, which can include some of the newer medicines like immunotherapies. We want to try to help people address the immediate need for out-of-pocket costs, but we also want to try to help them moving forward. If they’re in a position where they can change plans and actually lower their out-of-pocket, at least we can help address the ongoing financial burden and then just help people address the current cost that they have. Talking with the health care team is going to be very important to address those costs because they might have suggestions on how they can help lower (them). One of those could be talking with the pharmaceutical company that makes that particular drug. There are copay assistance programs that those companies offer to patients to help reduce the copays and other out-of-pocket costs that someone might be experiencing. There are also private foundations and organizations that have financial assistance programs to address those costs.

Are there any private foundations you can highlight here?

Patients can look specifically at cancer-related organizations that are specific to a type of cancer. For example, if you have leukemia or lymphoma, you can look at the Leukemia & Lymphoma Society for their assistance programs. Then, there are organizations that are not disease specific. They include the PAN Foundation or the HealthWell Foundation, which provide different types of financial assistance to help offset those out-of-pocket costs.

What are the top three pieces of advice you can give to patients?

I would say the first thing is to talk with your health care team; express your concern about what it’s going to cost and see if they have suggestions on how to address those financial expenses. The second is to reach out if you need help paying for the bills, because there is help available, but you have to seek it out. You have to actually ask for the help. The third is if you get denied because your health insurance plan refuses to cover your immunotherapy, you should appeal that decision. I often talk about the appeals process as the best-kept secret of our health care system, because most people take no for an answer, and unfortunately, that places a huge burden on patients.

We know that about 42 million claims were denied in 2019, and only 0.02% of those claims were actually appealed. So that’s about 200,000 claims out of 42 million, but we know that when people go through the appeals process and get external appeals, about 50% of the time, across the country, patients are winning those appeals and getting their care covered by their insurance company. Fifty percent of these 42 million claims is about 20 million people who could have gotten their care covered by their insurance company, which means that about 20 million people either paid for care out of pocket that their insurance company should have paid for, which obviously contributes to the financial burden, or they just didn’t get the care because they couldn’t afford to. That’s really tragic — that people aren’t getting access to the care that their health care team prescribed, and they don’t know their rights to appeal.

To avoid the financial burden of costly therapies, patients with cancer receiving immunotherapy treatments should talk with their health care team and not settle for no as an answer from their health insurance provider, according to an expert.

Immunotherapy Special Issue 2021 | CURE