Seeking Immunity: Exploring Kaposi's Sarcoma

Alex C.* was a teenager in 2007 when doctors told him he had Crohn’s disease, a chronic inflammatory intestinal condition that causes abdominal pain, diarrhea, weight loss, anemia and fatigue. For more than a decade, Alex managed the disease with lifestyle changes and medication. Then, in the summer of 2018, he unexpectedly lost weight, dropping from 135 pounds to 115 inside of six weeks. He felt weak and fatigued, some nights awaking drenched in sweat. Suspecting worsening Crohn’s, his doctor ordered a colonoscopy.

“When I woke up from the procedure, I could tell the doctors knew something was wrong,” Alex, now 25, says. Because he does not have HIV, he was unprepared to learn he had a rare cancer that usually strikes people who have the virus: Kaposi’s sarcoma, sometimes called KS.

Kaposi’s sarcoma forms from cells in the lining of blood and lymphatic vessels. “KS is different from other cancers in that it usually arises in multiple sites throughout the body, rather than arising from one malignant cell,” says Dr. Robert Yarchoan, chief of the HIV and AIDS Malignancy Branch at the Center for Cancer Research and director of the Office of HIV and AIDS Malignancy at the National Cancer Institute (NCI).

Kaposi’s sarcoma is very rare in the United States. Experts estimate that each year, about six out of 1 million Americans receive the diagnosis. It’s especially rare among young people like Alex who are HIV-negative. The reasons: Kaposi’s sarcoma develops only among the small group of Americans who have human herpesvirus 8, also called Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, it usually develops in individuals who also have an immunodeficiency such as HIV; in some cases, it is associated with lost immune function due to older age.

“In the United States, only about 5% of the population is infected with KSHV,” says Dr. Thomas Uldrick Jr., deputy head of global oncology at Fred Hutchinson Cancer Research Center in Seattle. However, certain groups of people in the U.S., such as gay men and immigrants from Africa, are more likely to be infected. Most don’t realize they have KSHV, because the immune system keeps it in check. But in people with a weakened immune system, like Alex, KSHV seems to multiply and trigger Kaposi’s sarcoma.

Doctors usually diagnose Kaposi’s sarcoma when lesions appear on the skin or in other areas of the body, such as inside the mouth, rectum or eyelids. In some cases, the cancer isn’t detected until the lesions cause symptoms. Lesions in the mouth and throat can make swallowing difficult, those in the lungs can interfere with breathing, and those in the digestive tract can cause abdominal pain and discomfort. Sometimes the lesions bleed, which can lead to low red blood cell counts and symptoms such as fatigue and shortness of breath.

Alex’s primary symptom was almost hourly diarrhea, leaving him sleep-deprived, malnourished and severely dehydrated. He was admitted to the hospital, where doctors discovered he was battling multiple infections, including E. coli, norovirus and, of course, Kaposi’s sarcoma. “I kept waiting to wake up from this bad dream,” he says.

Kaposi’s sarcoma can be mild or severe. It can strike one area of the body or pop up spontaneously in multiple locations. With the advent of antiviral medications for HIV and effective chemotherapy drugs for Kaposi’s sarcoma, the cancer is rarely a death sentence in the United States. The five-year survival rate hovers between 70% and 80%. However, in sub-Saharan Africa, Kaposi’s sarcoma is often more severe, and patients with HIV and Kaposi’s sarcoma are more likely to die than HIV-infected patients without Kaposi’s sarcoma.

Scientists still don’t understand why some people with KSHV are more likely to develop Kaposi’s sarcoma or why it often returns after treatment. Many people have recurrent disease for years and require multiple treatment courses. Fortunately, with novel treatment options and combination therapies, the future has never looked brighter for people affected by this rare cancer.

A HISTORICAL LOOK AT KAPOSI’S SARCOMA

Kaposi’s sarcoma first appeared in the medical lexicon in 1872, when Moritz Kaposi noticed skin lesions occurring in elderly men in Vienna. The men were likely infected with KSHV as children, and Kaposi’s sarcoma emerged as a result of a natural age-related decline in immune function, Yarchoan says.

Fast-forward to the beginning of the AIDS epidemic in 1981, when the Centers for Disease Control and Prevention (CDC) noted a new disease occurring primarily among young gay men in New York and California. Besides having AIDS, these men often developed Kaposi’s sarcoma along with infections, such as pneumocystis pneumonia, previously seen only in immunosuppressed people.

“Among AIDS patients, we recognized that men who had sex with men tended to get Kaposi’s sarcoma, whereas people who were injection drug users or had gotten AIDS from a blood transfusion didn’t get it,” says Yarchoan, who was an NCI investigator at the time. “This suggested that there was a second infectious agent causing KS that was not necessarily spread by blood but was spread by sexual contact.”

That second agent, KSHV, was discovered in 1994 by the husband-wife team of Drs. Patrick Moore and Yuan Chang. Like Epstein-Barr virus, best known for causing mononucleosis (aka the kissing disease), KSHV is spread through saliva. Both are evolutionarily old viruses, but for reasons that are not well understood, KSHV seems to be more tightly tied to specific regions of the world, such as sub-Saharan Africa, Eastern Europe and the western Mediterranean.

Although scientists recognized four types of Kaposi’s sarcoma, they now understand that all are part of the same disease. All four result from infection with KSHV — and, in many cases, a weakened immune system.

Classic: Classic Kaposi’s sarcoma typically strikes older men of Eastern European, Middle Eastern or Mediterranean descent. “Lesions typically occur on the lower legs, ankles and feet, and they’re usually slow growing,” says Dr. Gary Schwartz, chief of hematology/ oncology at NewYork-Presbyterian/Columbia University Irving Medical Center and deputy director of the Herbert Irving Comprehensive Cancer Center. The elderly are at greater risk of classic Kaposi’s sarcoma because the immune system naturally weakens with age.

Endemic: In regions of sub-Saharan Africa, up to 80% of the population is infected with KSHV. Because the virus is secreted in saliva, researchers think it’s spread by cultural practices, such as sharing food and utensils and chewing food to soften it before giving it to children. These regions are also vulnerable to malaria, chronic infections and malnutrition, which can affect the immune system and make people more susceptible to the cancer. “KS is the leading cause of death among people under 45 in Uganda, and it’s the second cause of death in adolescents and young adults in South Africa,” Uldrick says.

Epidemic: Kaposi’s sarcoma that develops in association with HIV infection is called epidemic Kaposi’s sarcoma. The cancer was first recognized when AIDS was a new disorder in 1981, and its incidence increased 20-fold, peaking at about 47 cases per 1 million people per year by the early 1990s. Kaposi’s sarcoma among this population used to be fatal, but after Yarchoan and his team developed the first antiretroviral drugs for HIV/ AIDS, they discovered that it helped some people with the cancer get better. “Now, antiretroviral therapy is the mainstay of treatment for HIV, and the incidence of HIV-associated KS has dropped 80%,” Uldrick says. For most patients with AIDS, antiretroviral therapy keeps the immune system functioning better so that Kaposi’s sarcoma never develops.

Iatrogenic: People who receive an organ transplant or take immunosuppressive therapy for a disease like Crohn’s are at risk of developing Kaposi’s sarcoma if they or the organ donor is infected with KSHV. Some patients have developed Kaposi’s sarcoma from donor cells. The disease tends to be milder in these patients than in those with AIDS/HIV, but treatment is still tricky. “Usually, there’s a delicate dance between lowering the immunosuppression to allow their immune system to control the KS, then increasing it again so they don’t reject their organ or suffer from a disease flare,” says Dr. Katherine A. Thornton, clinical director of the Sarcoma Center at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School in Boston.

UNIQUE CHALLENGES

Kaposi’s sarcoma isn’t assigned a stage the way other cancers are. For people with AIDS, doctors consider the extent of the cancer, the state of the immune system and how sick the patient is from Kaposi’s sarcoma or HIV. Whether bulky (spread out) or mild (localized), therapy for all types of Kaposi’s sarcoma is largely the same: focused on treating active disease and simultaneously bolstering the immune system when possible.

In people with AIDS-related Kaposi’s sarcoma, the first line of therapy is HIV treatment with antiretroviral drugs. In many cases, this approach is sufficient, but in more severe cases, it should be combined with chemotherapy or other cancer-specific therapy. With organ-transplant patients, doctors can sometimes resolve Kaposi’s sarcoma by lowering the dose of immunosuppressive drugs or changing the drug. In elderly men with classic Kaposi’s sarcoma who have contained disease, doctors can sometimes treat lesions with localized therapies such as radiation, cryotherapy (freezing the lesion) or intralesional chemotherapy (injecting a small amount of chemotherapy into the lesion).

“Since there’s always the possibility that these lesions will come back, oncologists are inclined to prescribe systemic chemotherapy, but it must be done in combination with antiretroviral therapy,” Schwartz says. The most common chemotherapy for Kaposi’s sarcoma is Doxil (liposomal doxorubicin). With Doxil, chemotherapy is encased in a pouch made of fat, or liposome. Because the liposomes build up preferentially in Kaposi’s sarcoma lesions compared with healthy tissue, they produce fewer side effects.

“A very low dose of Doxil can be very effective in up to 60% of people with KS,” Schwartz says. “In some patients, you can stop therapy after eight months or a year, and people have complete remissions that are very durable.”

Alex had bulky Kaposi’s sarcoma, so doctors prescribed eight rounds of Doxil (one hourlong infusion a month). Alex’s side effects were tolerable during the first several rounds — despite nausea and fatigue, he could work and maintain daily activities. The last few rounds of chemo- therapy were more challenging because he developed mouth sores and experienced periodic nausea and hair loss.

When patients don’t respond to Doxil, doctors may try another form of chemotherapy called Taxol (paclitaxel). Researchers have been testing other drugs that block new blood vessel formation, but these agents have not been particularly effective, and some have been toxic.

“Since KS is caused by a virus, lesions often come back, so you sometimes have to treat KS again and again,” Yarchoan says. That can create other problems: Patients can experience cumulative toxicity from repeated rounds of chemotherapy, such as heart-related side effects from anthracyclines, and the drugs can damage the immune system.

To complicate matters, KSHV can also infect other types of cells, including B cells, which play a critical role in other diseases. They’re the cells that produce antibodies, an important line of defense against infections. When B cells are infected with KSHV, patients face a higher risk of developing other malignancies, such as primary B-cell lymphoma and Castleman disease, a rare lymph node condition that can develop into lymphoma. These Kaposi’s sarcoma-associated diseases can also produce factors that fuel KS, causing it to grow and spread.

Castleman disease often leads to a high fever and low blood cell count, and the patient’s body becomes increasingly vulnerable to secondary infections. “Prior to effective treatments for both HIV and for Castleman disease, the average survival was just 14 months,” Uldrick says.

“Furthermore, doctors often do not recognize this rare disease. I think we’re underdiagnosing Castleman disease and maybe other malignancies because people die before they’re diagnosed.”

Fortunately, Alex avoided that fate. Within three months of his Kaposi’s sarcoma diagnosis, he enrolled in a clinical trial at the National Institutes of Health (NIH), where doctors gave him a diagnosis of Castleman on the spot. “I didn’t even want to share the name of the disease with my parents because I knew they would Google it,” he says, “and what they would find would be utterly devastating.”

Contrary to what shows up in an online search, physicians have made tremendous progress in developing treatments for Castleman disease. Doctors treated Alex’s case alongside Kaposi’s sarcoma with a secondary drug called Rituxan (rituximab), an antibody therapy that attaches to a specific protein (CD20) on the surface of B cells that contributes to Castleman; this kills the cells. “With rituximab, 90% of patients with Castleman disease have long-term survival,” Uldrick says, “so it makes a huge difference whether you diagnose it in time.”

Unfortunately, Rituxan sometimes activates Kaposi’s sarcoma. NIH investigators are exploring whether combining it with Doxil, which hits both the B cells and the sarcoma, can be useful in patients with these diseases. Preliminary results are very promising, Yarchoan says.

TOWARD A FUNCTIONAL CURE

One of the first drugs used to treat Kaposi’s sarcoma, interferon alpha, worked in part by activating the immune system cells that attack and destroy the virus. Unfortunately, the treatment worked only in people with solid immune systems — and then only about half the time. It also produces flu-like side effects. “But in classic KS patients with localized lesions on the skin, interferon injections have been successful, suggesting there may be a role for immunotherapy to treat this disease,” Schwartz says.

Unlike radiation and chemotherapy, which target cancer directly, immunotherapy recruits the patient’s immune system to fight cancer. Because patients with Kaposi’s sarcoma have immunodeficiencies, researchers wondered if immunotherapy could work in patients whose disease did not respond to other treatments. “The answer seems to be yes,” Yarchoan says.

If you look at patients whose Kaposi’s sarcoma resolves with antiretroviral therapy alone, their reconstituted immune system controls the cancer. In patients with bulkier Kaposi’s sarcoma, however, chemotherapy can introduce problems with the immune system. “You’re defeating the KS, but you’re not allowing the immune system to reconstitute,” Uldrick says. “So, there’s a large group of patients who need additional immune support to get them out of this cycle of periodic chemotherapy.”

One immunotherapy drug, the checkpoint inhibitor Keytruda (pembrolizumab), has already shown promise in a handful of patients with HIV. In 2019, NIH researchers reported that patients with well-controlled HIV tolerated immunotherapy well. “We saw people responding to immunotherapy across a range of CD4 counts (an indicator of immune system function),” Uldrick says. “So, at least at the anecdotal level, you can’t tell by someone’s CD4 count whether or not they’re going to respond to a checkpoint inhibitor.” Uldrick and his colleagues are recruiting patients for a study to determine whether using Keytruda in patients with HIV-associated Kaposi’s sarcoma before chemotherapy can help them sidestep chemotherapy or at least reduce their need for it.

“As the field gets stronger, we need to think about ways to augment the immune system above and beyond anti- retroviral therapy for people who are HIV-positive. Those same tools may work for people who are HIV-negative, as well,” Uldrick says.

Scientists are now testing another immunotherapy drug for the treatment of Kaposi’s sarcoma — Pomalyst (pomalidomide), an analogue of thalidomide. A number of years ago, Yarchoan and his team showed that thalidomide was active in Kaposi’s sarcoma, but at the doses used, it was associated with side effects. Working with Celgene, they recently tested Pomalyst and reported a 73% response rate with acceptable associated side effects. The drug-maker received breakthrough therapy designation (a promise of expedited review) from the Food and Drug Administration for Pomalyst in Kaposi’s sarcoma and plans to seek the agency’s approval.

One of the frustrations for individuals with Kaposi’s sarcoma is the rarity of these tumors. Patients often feel isolated because there are few experts in the field. “It’s a really hard place for a person to exist,” Thornton says. “People just want answers about what to do, but the data is sparse.”

Nevertheless, as far as rare cancers go Kaposi’s sarcoma is an inspiring story. In the age of antiretroviral therapy, chemotherapy and now immunotherapy, even people with bulky tumors like Alex’s are experiencing long-term remissions. Just last month, Alex received another call from his doctor, this time with good news: There’s no remaining evidence of Kaposi’s sarcoma.

“I know KS will never be off the table because I have KSHV, but I also know that doctors have more options than ever before to control the disease,” he says. So even though the most commonly prescribed medications for Crohn’s disease are not compatible with KSHV, Alex is entering a brave new world, and he’s armed with a new perspective.

“When I stopped trying to understand it, I came out on the other side with a new appreciation for the small joys in the world and an ability to accept almost anything that’s going on in my life with a sort of serenity,” Alex says. “The journey leaves scars, but it taught me about my strengths, expanded my capacity for love and brought me closer to a truer version of myself than I have ever known.”

*Name changed for anonymity by request.