and surgical procedures are refined, treatment options continue to expand for people with the most common cancer type, diseases of the skin.

®, Dr. Jeremy Brauer, a dermatologist at NYU Langone Health in New York City and a spokesperson for the Skin Cancer Foundation, reviewed the latest strategies for treating these cancers, which include squamous cell and basal cell carcinomas, as well as the less common but more aggressive melanoma.

: What surgical strategies are used to treat skin cancers?

The intervention with the highest cure rate for surgical procedures is Mohs micrographic surgery. This is ideal for nonmelanoma skin cancers specifically, but there also is growing interest and use in certain melanomas, depending on the skin cancer and its location.

(Tissue is removed and tested a little at a time until the area being treated is free of cancerous cells).

There’s no leaving the office and waiting a week for your results; everything is done on-site in real-time. We process the tissue, and a Mohs surgeon also functions as the pathologist to read the slides and map out where the tumor is or isn’t. The benefit of this is that it allows for tissue conservation, (especially on) the tip of the nose and ears. Also, it has a higher cure rate with the good cosmetic outcome because you are sparing tissue.

Another surgical intervention is a standard excision. You excise, take a big piece of skin and put stitches in, just like you would with Mohs, but it’s not a staged procedure. In general, it’s just one procedure.

Could you describe some of the nonsurgical therapies?

Nonsurgical treatments include electrodesiccation and curettage. These tend to be reserved for individuals who have a superficial basal cell carcinoma or what we call in situ squamous cell carcinoma, where the lesion is very superficial and on the uppermost part of the skin. Here, we use a sharp tool called a curette to scrape the area of involvement, but we also use electrodesiccation to burn the surrounding skin. This is often repeated in series a few times to remove the majority, if not all, of the tumor.

The goal here is to avoid having to cut and sew. The drawback is that you can’t evaluate the tissue under the microscope because you’re scraping and burning the remaining tumor cells.

Another nonsurgical option is radiation therapy. This is sometimes used in conjunction with surgical treatment if it is determined that the subtype of skin cancer warrants it.

If involvement of the nerves is found during the course of Mohs surgery or when the specimen comes back after incision, we refer the individual to receive concurrent radiation therapy.

Radiation therapy is also good for (skin cancer that is not being treated with surgery). In certain instances, the individual might not able to tolerate (surgery) or declines the procedure. Similarly, certain tumors that don’t heal well may be better candidates for a nonsurgical option.

Which medical options do you consider the most exciting?

I really do believe immunotherapy and targeted therapies for metastatic disease have been game changers. We consider immunotherapy an option for melanoma. It’s been a game changer for ... survival in advanced cancers. That has definitely prolonged life for many individuals who unfortunately otherwise would not have fared as well.

Another interesting and promising area is targeted therapy. Here, we’re looking at the identification within the tumor of a mutation, specifically in a gene or pathway, and then targeting that gene or pathway (with medication). This has also led to increased survival rates and really allowed for a change in the way we approach some of the more advanced tumors.

That said, early intervention is key. Once we’ve detected these skin cancers, early intervention results in very high cure rates and, hopefully, prevents some of these local tumors from becoming metastatic or advanced.

What is on the horizon for patients with skin cancer? 

Patients can be encouraged by the fact that medicine, technology and innovation are all moving at a very fast pace. More immunotherapy and targeted therapies will be made available to individuals with metastatic melanoma and advanced squamous cell carcinoma.

Also, right now, a biopsy is invasive. There is numbing and taking a blade to the skin. But there are other imaging techniques, and as our ability to detect skin cancer becomes better and greater, we’ll begin to see additional noninvasive biopsy techniques.

How can patients become empowered to be their own best advocates when making treatment decisions?

It starts with education. Knowledge is power. A great resource is a board-certified dermatologist, who can discuss in detail the diagnosis and expectations. Also, reputable websites like that of the Skin Cancer Foundation offer information. Within dermatology, the American Academy of Dermatology and other societies can be great resources.

Going back to prevention, people need to understand that skin cancer is serious. You can die from skin cancer. But the good news is that these are preventable tumors and cancers. You have to take action to prevent it.

How do you do that? (It takes) appropriate use of UVA- or UVB-spectrum sunscreen, sun-protected behaviors when outdoors and screening, not just seeing a dermatologist once a year but also doing monthly self-skin examinations. Look for something new, unusual or changing and bring that to the attention of a dermatologist. Early detection results in early intervention, which results in very high cure rates.

Articles

Speaking Out

Patients can pick from a growing array of treatments, from same-day- results surgery to game-changing immunotherapy, to fight the most common type of cancer.
 

Speaking Out: Taking Action Against Skin Cancer

When Teresa Byrd stepped out of the shower in February 2012, she noticed an ominous black mole, about half the size of a pencil eraser, toward the back of her right shoulder. A former hairstylist in rural Missouri who was then 44, Byrd had grown up living on a farm and baking in the sun. She had never been to a dermatologist.

“The way I was raised, we didn’t go to the doctor unless we were in pain,” Byrd says. Still, she was concerned and made an appointment with a local dermatologist. “He took one look and said, ‘I’m almost certain it’s cancer,’” she recalls. Two weeks later, Byrd received the official diagnosis: melanoma.

An estimated 100,000 Americans receive melanoma diagnoses each year. Once incurable in advanced stages with dismal survival rates, the disease has emerged as one of the most responsive cancers to immunotherapy, a treatment that harnesses the power of the immune system to fight cancer.

“Despite the best application of surgery, radiation and chemotherapy, 600,000 Americans die of cancer each year. Immunotherapy has become a fourth arm that has been very effective at treating cancer, especially melanoma,” says Dr. Steven Rosenberg, a senior investigator at the National Cancer Institute (NCI) who has been instrumental in advancing immunotherapy research for nearly 40 years. This category of treatment includes approaches ranging from checkpoint inhibitors and vaccines to cell-based strategies, including techniques like tumor-infiltrating lymphocyte (TIL) therapy, which multiplies a patient’s own cancer-fighting immune cells so they can better attack the disease.

Because Byrd’s cancer had spread to her lymph nodes and adrenal glands, she began an aggressive course of early immunotherapy called interferon. “I took a shot every Sunday night for a year,” Byrd says. “I called it the devil drug because it made every part of my body ache for several days each week.”

Interferon held Byrd’s cancer at bay until 2013, when a knot she discovered under her arm seemed to double in size by the day. Doctors treated her with 25 rounds of radiation, followed by immunotherapy with the checkpoint inhibitor Yervoy (ipilimumab) in 2014, but the cancer continued to spread. “My oncologist leaned back in his chair, put his arms behind his head and said, ‘There’s nothing more we can do for you,’” Byrd says.

When the couple left the oncologist’s office on Oct. 7, 2015, Byrd’s husband, Wesley, called The University of Texas MD Anderson Cancer Center in Houston. A clinical trial preparing to start would be investigating a new therapy; if MD Anderson doctors could tide her over until January, she would be eligible to participate.

Enter TIL therapy, a form of adoptive cell treatment that relies on patients’ own fighter T cells, a type of white cells called lymphocytes, to obliterate solid tumors. Doctors remove a metastatic tumor, identify the fighter T cells that already recognize and attack the cancer, grow them by the billions in the lab, and then infuse them back into the patient to launch a sustained attack.

It sounds like science fiction, but scientists are increasingly discovering that TIL therapy is not only possible but also could offer the best chance of durable remission among a subset of patients with hard-to-treat disease. “What better place to find cells doing battle against cancer than within the cancer itself?” Rosenberg asks.

Dating back to 1988, Rosenberg’s team showed that extracting lymphocytes from newly removed melanomas, expanding them in the lab and using interleukin 2 (IL-2), a lymphocyte growth factor, to further boost T-cell activity could produce impressive response rates.

“That was the first direct demonstration that T cells were responsible for immunotherapy-mediated rejection of cancer,” Rosenberg says. His team went on to treat hundreds of individuals who had melanoma with TILs and discovered that nearly 40% of patients experience durable remissions and long-term survival. The latest research suggests that TIL therapy may produce results in other cancer types.

Unlike chimeric antigen receptor T-cell therapy, which is approved to treat some blood cancers and relies on genetically engineered immune cells to battle disease, TIL therapy recruits the patient’s unaltered T cells — but only the rare subset demonstrating a natural ability to zero in on the cancer. The rub: “Doctors have to deplete the patient’s immune system so that, when you infuse the TILs back into patients, they don’t have to compete against other immune cells for resources,” says Dr. Amod Sarnaik, a surgical oncologist at Moffitt Cancer Center in Tampa, Florida.

To temporarily annihilate any cancer cells circulating in the blood, patients go on lymphodepleting chemotherapy, which is essentially an amped-up regimen. Side effects include diarrhea, vomiting, mouth sores and debilitating fatigue. Patients may also experience anemia and reduced platelet and white cell counts.

The treatment is so grueling and the risk of opportunistic infection so great that patients are often hospitalized until after their TIL infusion takes place seven to 10 days later.

In November 2015, doctors at MD Anderson removed a piece of Byrd’s tumor from her lung, separated out the fighter T cells and began growing them in a facility lab. To complete the treatment, the Byrds moved to Houston in February 2016, leaving their youngest son at home during his senior year of high school with their oldest son, who was student teaching at a nearby school.

“I was gone for so much of Collin’s senior year,” Byrd says. “Colton, my oldest, recorded every event, every basketball game, every important moment. They would even FaceTime me and tell me what they were fixing for supper.”

While Byrd pushed through chemotherapy, scientists grew her T cells in the lab, expanding the count to 20.1 million. Then, on her husband’s 48th birthday, it was party time. “Everyone from the nurses to the doctors to the laboratory technicians came to my hospital room,” Byrd says. “It was like a big celebration. Our friends had planned to surprise Wesley with a birthday party in my room. They brought in pizza and beverages at the same time doctors came into my room with the infusion bag.”

Byrd wasn’t out of the woods yet. After TIL therapy, patients receive treatment with IL-2, a protein called a cytokine that helps the fighter T cells grow. It’s the same agent used in the lab to spur TILs to multiply. “IL-2 stimulates the T cells that have been infused back into the patient to grow and establish themselves as part of the patient’s immune system,” says Dr. Amir Jazaeri, director of the gynecologic cancer immunotherapy program at MD Anderson.

T cells sometimes cause fever and chills as they’re being infused, and the IL-2 administered afterward has potentially significant side effects, including changes in blood pressure and heart rate. Some patients even require treatment in the intensive care unit. “The chills and shakes were so violent that Wesley had to put a stocking hat on my head and a scarf around my neck.

I was layered in three heated blankets, and when the chills started up, he would sit on the bottom of my legs so I wouldn’t fall off the bed,” Byrd says.

Most of the side effects of treatment occur during the hospital stay and shortly thereafter. Because it’s a one-time treatment, the more time that passes after the T-cell infusion, the fewer the significant side effects. That’s a departure from immune checkpoint inhibitors, infused drugs that disable certain proteins to activate the immune system against cancer; patients need to stay on that treatment for months or even years at a time. As a result, “with checkpoint inhibitors, the onset of side effects could happen months after starting therapy,” Jazaeri says.

By the end of March 2016, Byrd was back home, preparing for her son’s high school graduation, and she hasn’t been on any therapy since. “It was one of the most emotional moments of my life,” Byrd says. “I didn’t realize how hard my illness was for my son until graduation, but I think the experience made us feel stronger and closer as a family.”

With the help of the single TIL treatment, Byrd’s body continued fighting the cancer for the next four years. As of February 2020, she has had no evidence of disease.

The success of TIL therapy rests largely on whether scientists can identify mutations inside the tumor. This allows them to test which T cells are able to recognize and attack the “drivers” of a cancer and then focus on multiplying that special population of immune cells in the lab.

Melanoma is the low-hanging fruit of immunotherapy targets because it’s usually induced by ultraviolet radiation and resulting DNA damage. “That’s why melanoma has a much higher rate of mutations compared to other types of cancers,” Sarnaik says. It also allows the immune system to distinguish a melanoma cancer cell from a normal cell, just as it would recognize bacteria or viruses.

Scientists are investigating whether cervical cancer would also be amenable to TIL therapy, because about 90% of these cancers are caused by HPV. “Cervical cancer doesn’t have the high mutational burden of melanoma, but it can still display targets on the surface of the tumor cells because it tends to be caused by a virus,” Sarnaik says. That makes it more detectable by the immune system.

Iovance Biotherapeutics in San Carlos, California, is already proving to be a leader in this space, with TIL technology in phase 3 clinical trials for advanced cervical cancer and metastatic melanoma. In May 2019, the company reported a 44% response rate among 27 women with advanced cervical cancer that had progressed on previous treatments, including three patients whose disease disappeared. Among 66 melanoma patients, 38% responded, including two who had no evidence of disease.

Rosenberg emphasizes that this kind of treatment is not cancer type-specific. The past decade brought an explosion of trials investigating whether TIL therapy may have a role in various cancers, including breast, colorectal and head and neck. “All cancers have mutations. The key is targeting them effectively,” he says.

That can be tricky, especially for common epithelial cancers. These types, which represent about 90% of new cancer diagnoses in the United States, begin in the cells that line organs such as the breasts, lungs and ovaries. Although Rosenberg’s team has developed highly selective techniques to identify the rare immune cells in these tumors that recognize the cancer, they amount to about 1 in every 10,000 to 1 in every 100,000 lymphocytes — like a needle in a haystack.

Even with these minuscule numbers, if doctors identify the right lymphocytes and expand them in the lab by the billions, some patients can achieve durable response rates. Judy Perkins, a nature lover and former engineer from Port St. Lucie, Florida, is just one example.

She received a diagnosis of stage 0 breast cancer in 2003, and her only treatment was surgery. A decade later, when her youngest child was graduating from eighth grade and her oldest was a high school sophomore, Perkins’ breast cancer returned. For two years she tried hormonal therapies and chemotherapies. She had even been in a clinical trial for a targeted drug called lucitanib. When those treatments failed and doctors told her she had only a few months to live, she started working on her bucket list.

“I spent as much time with my friends and family as I could. I intended to curl up with my cats and read books or watch TV until I died,” says Perkins, who was 50 at the time. A lobbyist and advocate for breast cancer research, Perkins decided to attend one last training conference: Project LEAD, sponsored by the National Breast Cancer Coalition. While there, she learned that an NCI-sponsored clinical trial was underway to investigate TIL therapy in metastatic cancers.

To be eligible, patients had to have at least two tumors, one to be removed to obtain the TIL and one for doctors to monitor to see if the treatment was working. Perkins was a good candidate because, unlike many other patients with breast cancer, she had tumors to work with. “Patients with (advanced) breast cancer often have bone-only disease. By the time they develop tumors that can be surgically removed, usually in the liver and lungs, patients are too sick to tolerate treatment,” Perkins says.

A few weeks after the training, scientists sequenced DNA and RNA from one of Perkins’ tumors, as well as normal tissue to determine which mutations were unique to her cancer. They identified 62 mutations in her tumor cells. The TILs recognized four of them. Researchers expanded those four TILs to 81 billion in the lab before reinfusing them back into Perkins.

Between her surgery in August 2015 and when the multiplied TILs were ready in December, Perkins had deteriorated dramatically. By the time she arrived at the National Institutes of Health, she was in a lot of pain and tumors had spread throughout her liver. She knew the odds of the TILs working were less than 15%, but she also knew it was her last chance for a viable treatment.

“Within days, I could tell the tumor was getting softer and smaller,” Perkins says. “By February, I had a 60% reduction in tumor size. By April, I was backpacking on the Appalachian Trail. And in May, I had my first clean scan.” The cancer was gone and has been ever since.

Perkins is still an outlier for her ability to receive TIL therapy and her dramatic response; her case was featured in a 2018 paper in 

. Researchers have seen similar results using TIL treatment for patients in the same trial with other cancers, including liver, lung and colorectal. “For those of us who were fortunate enough to have a complete response, none of us have ever relapsed,” Perkins says.

TIL therapy, though decades in the making, is still in its infancy, and the process is complex. “It’s important to understand that TIL is still a highly experimental treatment that’s only available at a few institutions,” Rosenberg says.

The ultimate in personalized immunotherapy, TIL therapy requires customizing a treatment for each patient. The time-consuming and expensive endeavor is expected to cost about half a million dollars, rising to over $1 million when hospital stays are added. Before receiving treatment, patients have to wait for scientists to identify the effective lymphocytes and grow them in a lab, a process that can take months. Many people with aggressive, metastatic disease don’t have that kind of time.

Plus, people with advanced disease may not be able to tolerate the high-dose chemo- therapy required to deplete the immune system or the IL-2 needed to boost T-cell production after infusion. Therapy requires two to three weeks of inpatient treatment, and even under ideal circumstances, there are no guarantees that it will work.

“A lot of research is going into exploring the responders versus the non-responders,”

Jazaeri says. Studies suggest that younger patients have higher odds that their TILs will successfully multiply in the lab than other groups — 94% for patients under 30 compared with 46% for those over 60. Women, too, produce a higher TIL generation rate than men at 71% versus 57%, respectively. Byrd and Perkins, both women, were well under 60 when they underwent TIL infusion.

Researchers are working hard to iron out these kinks. Iovance has already halved the time it takes to make TIL therapy, from 42 days to 22. And as a one-and-done treatment for metastatic cancers, TIL therapy could save health care dollars over the long run. “If a treatment works, it has been my experience that the genius of American industry will find a way around obstacles like production time and cost,” Rosenberg says.

Feature

Across cancer types, a unique immune-stimulating treatment called tumor-infiltrating lymphocyte therapy produces durable remissions that could last for decades.
 

Unleashing the Power Within Using Tumor-Infiltrating Lymphocyte Therapy

After Susan Raphael received a diagnosis of pancreatic cancer in October 2018, she was treated successfully with surgery, radiation and 12 rounds of chemotherapy. Then, in February 2020, a PET scan revealed a Sister Mary Joseph nodule, a small abdominal lump near her navel that was a sign her disease had metastasized.

Raphael, who lives in Topanga, California, could have tried different chemotherapy, but her oncologists discovered a clinical trial that they believed offered a better chance of beating the disease. Participants receive a combination of two experimental drugs, along with the chemotherapy treatments nab-paclitaxel and gemcitabine.

One of the drugs is an immunotherapy that blocks PD-1, a so-called checkpoint protein that prevents the immune system from going into overdrive, making it difficult for immune cells to recognize and attack cancer. The other is a targeted drug that inhibits CD73, a protein that also suppresses the immune system and has been associated with a poor prognosis in several tumor types, including pancreatic cancer. Raphael receives the chemotherapy by infusion every week for three weeks and the immunotherapy and targeted drug every other week, taking a week off between cycles.

As of the end of April, Raphael’s nodule had shrunk and a blood test revealed a significant drop in her levels of carbohydrate antigen 19-9, a protein released by pancreatic cancer cells. She will remain on the regimen as long as her cancer responds to it.

Although she has had hair loss, stomach upset and anemia, the side effects have not prevented her from working full-time in the film industry and staying active outside of work. “I exercise every day, I’m painting, and I continue to work,” says Raphael, 64. “I have a lot of energy.”

Combination treatments offer new choices for treating patients with cancers that haven’t traditionally responded well to immunotherapy, including cancers of the gastrointestinal (GI) tract and breast and ovarian tumors. The combinations are designed to target specific characteristics of tumors, such as excess production of cancer-promoting proteins caused by genetic mutations, in ways that may make them more responsive to immune-boosting treatments.

Some immunotherapy combinations are already widely used to treat GI cancers. For example, in July 2018, the Food and Drug Administration (FDA) approved a pair of immune checkpoint inhibitors — Opdivo (nivolumab), aimed at PD-1, and Yervoy (ipilimumab), which blocks the protein CTLA-4 &mdash; for patients with metastatic colorectal cancer that is microsatellite instability (MSI)-high or mismatch repair deficient. Tumors with those characteristics have increased expression of neo-antigens, which makes them more visible to the immune system and, hence, potentially more amenable to treatment with checkpoint inhibitors.

A tumor’s MSI status can be measured with DNA sequencing or immunohistochemistry, which helps match eligible patients with immunotherapies and other targeted treatments. About 15% of colorectal cancers are MSI-high.

The FDA approval of Opdivo plus Yervoy was based on results from a trial involving 119 patients with colorectal cancer, 49% of whom responded to the combination. Among those responders, 19% were still well one year after starting the treatment.

The Opdivo-Yervoy combo has since been greenlighted to treat patients with hepatocellular carcinoma, the most common type of liver cancer. That approval was based on trial results in which 33% of the 49 patients who received the treatment responded, with 31% of those patients responding for at least two years. The mechanism of benefit is unclear, as MSI-high status is uncommon in liver cancer.

Researchers have started examining the potential of combining Opdivo and Yervoy in other GI cancers. In a trial involving 160 patients with metastatic gastric, esophageal or gastroesophageal junction cancer, with results published in 2018, 17% of participants taking one of the two doses that were tested experienced no disease progression for one year. Most of the participants had previously been treated with chemotherapy.

Now the National Cancer Institute is sponsoring a clinical trial investigating the potential of the combination, along with radiation and chemotherapy, in patients with earlier-stage disease, prior to surgical removal of their tumors. Another combination approaches showing efficacy in GI cancers involves VEGF inhibitors, or anti-angiogenesis drugs, which work in part by normalizing the leaky blood vessels that feed tumors. These drugs were initially developed to starve tumors of the oxygen and nutrients they need to survive but may also improve the ability of immune-boosting drugs like checkpoint inhibitors to treat tumors.

“The blood vessels in tumors are abnormal; they have a lot of holes in them,” says Dr. G. Dan Duda, associate professor of radiation oncology at Harvard Medical School and director of translational research in gastrointestinal radiation oncology at Massachusetts General Hospital in Boston. Fixing those leaks “creates better flow and improves tumor oxygenation,” he says, allowing immune cells to flood into the tumor and more efficiently attack the cancer.

In a trial pairing the VEGF inhibitor Avastin (bevacizumab) with the PD-L1 checkpoint blocker Tecentriq (atezolizumab), the time until disease progression in patients with hepatocellular carcinoma improved by an unprecedented 41% over treatment with the multikinase inhibitor Nexavar (sorafenib), a pan-VEGF receptor inhibitor. On May 29, the FDA approved the combination for the initial treatment of hepatocellular carcinoma that can’t be removed with surgery.

The strategy of combining Tecentriq with Avastin is also being investigated in colorectal cancer, both for treating MSI-high tumors and along with chemotherapy in all patients with metastatic disease regardless of MSI status. Moreover, combining Stivarga (regorafenib), another multikinase inhibitor drug, with Opdivo showed intriguing response rates in patients with colorectal and gastric cancers, and this combination is now being pursued in multiple trials in gastrointestinal cancers, Duda says.

Other strategies in the works combine immunotherapy with drugs that target the cancer-driving proteins generated due to certain gene mutations in tumors. A trial that completed last year tested the PD-1-inhibiting immunotherapy Keytruda (pembrolizumab) with the targeted drug Herceptin (trastuzumab) in patients with gastric cancer whose tumors had tested positive for HER2, a protein that is overexpressed and promotes growth in certain cancers, including gastric, breast and ovarian. Herceptin is already approved to treat patients with HER2-positive breast and gastric cancers.

In that trial, the combination treatment produced responses in 87% of 32 patients. It was particularly notable because just 47% of patients with HER2- positive gastric cancer in a large trial of Herceptin plus chemotherapy responded. Now several additional immunotherapy combination studies are underway in HER2-positive gastric cancer, including some that combine Keytruda and Herceptin with chemotherapy.

Blocking CD73, the strategy at the heart of the clinical trial that Raphael joined, could prove useful beyond GI cancers. CD73 plays an important role in the body’s production of adenosine, a substance in the tumor environment that dampens immune responses. Several studies underway are combining experimental anti-CD73 drugs with checkpoint inhibitors in triple-negative breast cancer, a particularly aggressive and hard-to-treat form of the disease. “The idea is to try to find a link between stimulating the immune system and making checkpoint inhibitors work better,” says Dr. Lee Schwartzberg, chief medical director of West Cancer Center and a professor of medicine at the University of Tennessee Health Science Center in Memphis.

Another potential strategy for achieving that synergy in triple-negative breast cancer involves combining checkpoint inhibition with drugs that inhibit a protein called poly (ADP-ribose) polymerase, or PARP, which cancer cells need to repair their DNA. In a phase 2 study using Keytruda plus the PARP inhibitor Zejula (niraparib) in 55 patients with metastatic triple-negative breast cancer, five participants had complete responses and another five showed partial responses.

The response was particularly strong in patients whose tumors harbored mutations in BRCA genes because these cells already have impaired DNA repair. Among the 15 participants with BRCA tumor mutations, seven had some response to the combination treatment.

The participants were also tested for PD-L1, a biomarker that helps identify patients who are likely to respond well to checkpoint inhibitors. Interestingly, although response was more pronounced in patients with PD-L1-positive tumors than those with PD-L1-negative tumors, there were strong responses in patients with both high and low levels of the protein. “This was intriguing, because checkpoint inhibitors by themselves have little activity in triple-negative breast cancer, particularly in late-line treatment,” Schwartzberg says.

Why does inhibiting PARP make breast tumors more amenable to checkpoint inhibition? Animal studies showed that PARP inhibitors stimulate a particular pathway that increases the activity of the immune system, according to Schwartzberg. “That allows checkpoint inhibitors to work better,” he says.

A trial of the same combination in chemotherapy- resistant ovarian cancer was also encouraging. Among the 62 participants, 11 responded to the treatment and 28 had stable disease. A study evaluating PARP and checkpoint inhibition together in ovarian cancer patients who do respond to chemotherapy recently started, this one combining Opdivo with the PARP inhibitor Rubraca (rucaparib).

The combination of anti-angiogenic drugs with checkpoint inhibitors that has shown promise in some GI cancers is now being tested in ovarian cancer. In a phase 2 trial combining Opdivo with Avastin in relapsed ovarian cancer, 11 of 38 participants responded. The rate was highes among patients who had a positive outcome after being treated with platinum-based chemotherapy.

Future studies of immuno-oncology combination treatments could help answer important questions about how genetic abnormalities influence patient responses. BRCA mutations, for example, can be inherited, known as germline mutations, or acquired, occurring solely in tumors. The trial combining Keytruda with the PARP inhibitor Zejula examined BRCA mutations in breast tumors but did not focus on germline mutations.

“We know that patients with germline BRCA mutations respond nicely to PARP inhibitors as monotherapy,” Schwartzberg says. Additional information about the role of germline BRCA mutations in response to combination treatments could help oncologists identify which patients are likely to respond well to them.

Future studies should also improve the understanding of how combining drugs that all work differently in the body can contribute to side effects. So far, most of the side effects reported in clinical trials of immuno-oncology combinations mirror those that are commonly reported with each drug alone. In some cases, in which a patient takes two checkpoint inhibitors, side effects could be significant, because immunotherapies that target CTLA4 are more toxic than those that target PD-1 or PD-L1. On the other hand, in the trial combining Keytruda with Zejula to treat breast cancer, common side effects were nausea and anemia, which were easily treated.

Raphael has so far experienced fewer side effects in the clinical trial combining chemotherapy with two experimental immuno-oncology drugs than she did during her initial treatment for pancreatic cancer, a harsh regimen of five chemotherapy drugs. “I’m back doing 7-mile hikes on the weekends, sometimes more,” Raphael says. “I’ve been active throughout. And I feel lucky to have had the opportunity to be in the trial. I did everything I could with conventional treatments, but now is the time to explore all the exciting new developments in immunology.”

New immunotherapy combinations aim to turbocharge the immune system’s attack against cancer.
 

Immunotherapy Special Issue 2020 | CURE

Speaking Out: Taking Action Against Skin Cancer

Unleashing the Power Within Using Tumor-Infiltrating Lymphocyte Therapy

New Immunotherapy Combinations Look to Create Maximum Velocity in Immune Systems Response to Cancer

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