Portal de Periódicos da CAPES

Strategies for Patients With Sarcomas & Merkel Cell Carcinoma

2023; Wolters Kluwer; Volume: 45; Issue: 9 Linguagem: Inglês

10.1097/01.cot.0000935940.98611.e7

1548-4688

Valerie Neff Newitt,

Bacteriophages and microbial interactions

Sarcoma, Merkel Cell Carcinoma: Sarcoma, Merkel Cell CarcinomaSandra P. D'Angelo, MD, Associate Attending Physician at Memorial Sloan Kettering Cancer Center in New York City, is a proud Italian American who offsets her appreciation of—and indulgence in—fine Italian cuisine with a love of running. When she's not enjoying her hobbies or home life as a wife and mother of two sons, D'Angelo specializes in the care of patients with soft tissue and bone sarcoma and Merkel cell carcinoma. Working closely with a multidisciplinary team of fellow medical oncologists, surgeons, radiation oncologists, nurses, and patient support advocates, she charges herself with providing optimum care for patients with those diseases.Sandra P. D'Angelo, MD: Sandra P. D'Angelo, MDIn addition to her clinical demands, D'Angelo is knee-deep in research focused on sarcoma, immunology, and cell therapy. “I am a member of the Cellular Therapeutics Service, which designs and conducts early clinical trials using investigational therapies that employ the body's own immune system to fight multiple types of cancer,” she told Oncology Times. Ultimately, she hopes to develop innovative strategies to use the immune system to treat rare cancers. All New York, All the Time D'Angelo describes herself as a “lifelong New Yorker” who has never wandered too far from home while finding her way into medicine. Her initial exposure was a summer job with her family practitioner who, like her parents, was an immigrant. “I worked in Dr. Nicholas' practice from high school up until I started medical school. She was my first mentor, one of my favorite people, and someone with whom I maintain close contact,” D'Angelo noted. Working in that office consolidated her interest in the medical field because she was struck by the intimacy of the patient/doctor relationship. “Eventually I did all my training in New York. I went to NYU for undergrad and then I went to SUNY Downstate Medical School in Brooklyn. It was at NYU that I had my first encounter with oncology,” she recalled. D'Angelo's first rotation as an intern was at Memorial Sloan Kettering. “I was night float for 2 weeks and then I was on the inpatient oncology service. I was traumatized initially; overwhelmed by those experiences,” she admitted. “But eventually, I circled back and did some outpatient rotation and began to realize the power of the institution, as well as the power of oncology itself. It's not just about the patient journey; the patient journey is really complemented by the research that's done in the field. It was this intersection between patient care, how it's heavily influenced by the need to appreciate the limitations of the standard of care currently available, and how we can modify and improve those standards of care that really excited me about oncology.” After finishing internal medicine training at NYU, D'Angelo was fully committed to pursuing oncology. She spent a year at Memorial Sloan Kettering as Chief Resident and had the opportunity to work with trainees, teach, and mentor, all of which consolidated her interest in remaining in the academic world. “After that year, I began my hematology-oncology fellowship at Memorial Sloan Kettering. There, I spent a year doing all clinical rotations, both inpatient and outpatient, in different specialties, and was exposed to the whole breadth of oncology care,” she explained. “Years 2 and 3 were research years. Given my patient-centered focus, I spent 2 years doing clinical research. And by default, with the fellowship I chose, I had that secured and protected time to conduct research.” Pivot Point Asked to explain a bit about her areas of specialization, D'Angelo said, “I'm going to step back and tell you how I landed in sarcoma. Initially, when I did my clinical research as a fellow at MSK, I had focused on lung cancer. When I finished my fellowship, I was committed to staying in New York. At Memorial Sloan Kettering, there was no position open in thoracic cancer. However, there had been a departure of one of the sarcoma faculty, resulting in an opening in the melanoma sarcoma service. So I just completely shifted gears and changed my focus. “At the time it was very frightening. I was abandoning the comfort level I had with lung cancer and a team I had worked with for 2 years. But later I realized that was the best career move of my life. Being flexible and open to change has allowed me to ask important questions in my life and in my research, and to grow and excel in different areas. That was an interesting pivot point for me.” Her new melanoma sarcoma team at Memorial Sloan Kettering decided to integrate Merkel cell, another skin cancer, into the research. “They tapped me saying, ‘Sandra, you're starting and you're going to see all the Merkel cell patients,’” D'Angelo recalled. “I thought, ‘Okay, it's something I've never done before, but I'm going to jump on it.’” Eventually, the melanoma and sarcoma services split and D'Angelo chose to align with sarcoma. “I specifically recall Dr. Bill Tap, our Sarcoma Service Chief, asking me if I would like to oversee an immunotherapy trial. Initially, I told him I wasn't familiar with immunotherapy and his reply was, ‘Don't be afraid to do something because you're afraid to learn.’ That was probably the best advice I received as a mentee. I quickly appreciated that the field of immunotherapy was blossoming and emerging in the melanoma field,” D'Angelo noted. “A lot of the signals of benefit with checkpoint blockade, and different therapeutic approaches, had just begun to take off. And I said, ‘Why don't I try and bring this research to sarcoma?’ And that's exactly what I did. It was another pivot point in my life, where I was forced to decide. But it wound up being an amazing decision because that was the beginning of all my research. I was able to then build an immunotherapy program using the guidance of all the various leaders at Memorial Sloan Kettering and emulate what they were successfully doing in melanoma. I am surrounded by strong and effective mentors such as Dr. Tap. He has always demonstrated the power of a strong sponsor. It truly requires a gentle balance of guiding mentees while allowing them to think independently. I strive to support my mentees in a similar fashion.” It took a lot of bravery on D'Angelo's part to tackle such a new area of specialization. However, she said she inherited that bravery from her parents who immigrated to this country in the 1960s. “I look at their experience as the ultimate challenge, right? Leaving their hometown and establishing themselves in this new world was difficult,” she said. “They didn't even speak English. And yet, somehow they figured it all out. So I always turn to their experience and say, ‘Well, they moved halfway across the world and worked it out.’ Having the same resilience and the same grit to succeed is something I hold very close to my heart.” The Research D'Angelo's research is based on immunotherapy in two ways. “One is concerned with standard checkpoint inhibition. There are drugs that are now FDA-approved for a number of different cancers, but we don't yet have approval in sarcoma,” she lamented. “The second focus is in the field of T-cell therapy or adopted cell therapy. This is a second approach I've been closely involved with in a specific sarcoma—synovial sarcoma—and myxoid/round cell liposarcoma. Those are diseases characterized by overexpression of cancer/testis antigens, proteins that typically are only expressed in abnormal cancer cells, but not in normal cells. Some examples of those are NY-ESO-1 or MAGE-A4. T cells designed to target these proteins have shown a lot of promise to date. There are a number of pivotal clinical trials underway with both compounds. One cell therapy trialed to target NY-ESO-1 is called a lete-cel, and a second one targeting MAGE-A4 is called afami-cel. Those clinical trials are enrolling and some of the early data has been promising. We hope they may evolve into the first FDA approvals for cell therapy in a rare cancer-like sarcoma.” The rarity of sarcoma is pegged to the fact that it is a very complex disease with 70-80 different types. “There are only about 12,000 cases of all sarcomas each year in the United States,” detailed D'Angelo, “compared to 200,000 cases of breast cancer each year. So we're dealing with a rare disease with many subtypes. Historically, we used to approach care with a one-size-fits-all attitude: all sarcomas were enrolled on the same clinical trial and received the same intervention. But we've come to realize that we need to split these diseases based on the underlying type of sarcoma that exists. And that's how a lot of the breakthroughs now are expected to evolve—through what we call a histology-specific approach.” Currently, the standard of care for sarcoma is surgery if the tumor is limited to just one area of the body. “If the tumors are big, radiation might be used,” D'Angelo said. “And then sometimes we use chemotherapy, all in the interest of preventing recurrence. But the sobering fact is about half of patients with tumors greater than 8 centimeters in size will die of metastatic and incurable disease. When it's advanced and has spread, the median survival is about a year and a half. So there's an unmet clinical need to figure out better ways to care for patients and offer them more options.” Rare Disease Turning to her work with Merkel cell carcinoma, D'Angelo said, “The success of immunotherapy in Merkel cell is actually what ties and informs the programs. Merkel cell is a very different type of cancer. It's a skin cancer essentially even rarer than some sarcoma subtypes. There are only about 2,000 cases of Merkel cell a year in the United States and only about 10 percent—200 cases—of those are actually metastatic. With Merkel cell, checkpoint inhibitors have risen to the forefront of care for patients. The response rate is 40-50 percent, so about one in two patients benefit from immunotherapy. But there remains an unmet clinical need for about 50 percent of patients for whom immunotherapy doesn't work.” There is also a fraction of patients who don't qualify for immunotherapy. “So within the Merkel cell space, we're focusing on trying to understand which patients benefit and which patients do not, and how we can improve response rates in those who don't respond,” D'Angelo shared. The work at hand requires a bidirectional flow of information, from the patient to the lab and then from the lab back to the patient. “That's the power of translational research, right?” D'Angelo asked, rhetorically. “One approach is to check the cell line, conduct the experiment in a mouse, and then bring that to the patient. Oftentimes, that can lead to lots of delays in bringing promising therapeutics to our patients. Those experiments can take years and years and years. An alternative approach is to bring it to the patient, obtain tissue biopsy specimens throughout the patient's treatment journey, and then bring that back to the lab. At MSK, we have a number of different collaborations with lab scientists who are able to complement the patient care piece of it.” Day to day, D'Angelo strives to bring new drugs to patients, opens clinical trials, and enrolls patients. “We obtain pretreatment biopsies before patients start therapy, and treatment biopsies while they're receiving therapy. And then, when the clinical trial has finished, I send the specimens to different labs at MSK, and we try to correlate the response to the changes we see in the lab,” she detailed. “So some of the questions of interest to me are: What happens to the immune microenvironment? Are we able to increase T cells or not? “As a clinical researcher, I don't do the work in the lab myself. I see the patient, enroll the patient in a clinical trial when it's appropriate, collaborate very closely with experts in each of the different disciplines that I'm interested in, and bring teams together to ask those important questions. “One of the first clinical trials that I ran through the Alliance Cooperative Group looked at a combination of two immunotherapy drugs. Now we're running a trial, ENVASARC, in hopes of leading to an FDA approval and impacting standard of care,” D'Angelo stated. “The checkpoint blockade was one of my first studies, and now we're at the point where we're running what we hope is a definitive and pivotal study.” Other important clinical trials with which D'Angelo has been involved since 2014 are T-cell therapy trials she hopes will lead to a breakthrough in the field. And yet another important investigation that is ongoing at MSK involves “...figuring out how to make immunotherapy more effective in each of the different types of sarcomas. My colleague, Mark Dickson, MD, has worked very closely in developing a class of drugs called CDK4 inhibitors. He ran some of the earliest clinical trials with a drug called palbociclib, which is FDA-approved for breast cancer. He ran a second clinical trial with a similar CDK4 inhibitor called abemaciclib. “Now, he's running a pivotal trial in liposarcoma to see if abemaciclib is better than placebo in patients with dedifferentiated liposarcoma,” D'Angelo stated. “Extrapolating some of the work that he has done, I am trying to combine an immunotherapy with palbociclib to see if we can make both approaches more effective than either one alone.” D'Angelo is also working closely with MSK's Andrew Koff, PhD, who has shown interesting data revealing that the way in which a cell dies, and what pathways it enters, can potentially make the environment more favorable to immunotherapy. Working with Samuel Singer, MD, Chief of the Gastric and Mixed Tumor Service, D'Angelo is looking at ways to detect changes in the microenvironment. “In his lab, we're doing single-cell sequencing to try and understand what changes occur as a result of this drug and if it truly will make immunotherapy more effective,” she explained. The Big Picture Considering how this body of research may be impactful on the field of oncology, D'Angelo paused thoughtfully before saying, “George J. Bosl, MD, MSK's former Chair of Medicine, instilled in me the understanding that everything we do, all of our decisions, must be accomplished in the context of patient care. Oncologists, caretakers, other health care providers should never lose sight of that. How patients' cancer does or doesn't respond to treatment will actually inform what we should do next. We learn from patients, and then that allows us to bring more to our patients. We learn, we see someone benefit from a therapy, and then we see another patient not benefit from a therapy. What is it about these two individual tumors that are so different? How can that guide us to figure out what strategy we use in the future?” D'Angelo stressed, “It always goes back to the power of the patient. The patient/physician relationship is the cornerstone of what I do day to day. Just the standard of care is not good enough for our patients. We need to be able to offer more. We can do that through various clinical trials. For patients, these trials provide hope and that is what is really important.” Valerie Neff Newitt is a contributing writer.