Closer to a Cure for Myeloma

Publication
Article
CURESpring 2018
Volume 1
Issue 1

In pretreated multiple myeloma, experimental CAR-T cell immunotherapy offers the potential for long-term — and possibly even permanent — remission.

Woodring “Woody” Wright found out he had multiple myeloma 12 years ago, when he sneezed and broke a vertebra that had been damaged by the cancer. Wright, who is a professor of cell biology at the University of Texas Southwestern Medical Center in Dallas, and his doctors fought the disease vigorously. But after a decade of treatment, he began to run out of options and contemplated looking into hospice.

Then Wright enrolled in a clinical trial of a “living drug” that was made by extracting some of his own immune cells, adding genetic code so they would recognize his myeloma and reintroducing these weaponized cells into his body to attack his cancer, a type generally thought to be incurable.

Today, more than two years later, Wright shows no evidence of multiple myeloma, is back to working on his research and considers himself cured. Even his doctors, who have more cautiously called his case a “sustained complete response,” are beginning to think that “cure” might not be too strong a word.

“I really do think that Woody might be cured,” says Adam D. Cohen, M.D., director of myeloma immunotherapy at the University of Pennsylvania in Philadelphia and lead author of the December 2017 abstract that reported the results of the study in which Wright participated. “We’re entering a new phase in treatment for myeloma. I can’t remember another time when there were so many phase 1 myeloma studies that had such a high response rate.”

MOVING INTO MYELOMA

Chimeric antigen receptor (CAR)-T cell therapies, such as the treatment Wright had, were initially developed for use in other blood cancers and approved by the Food and Drug Administration (FDA) for certain types of lymphoma and leukemia. Tailored versions engineered to recognize and fight different antigens are being tested in other malignancies, with some of the most promising data coming from trials that treat patients with multiple myeloma. Other teams are designing medications that link chemotherapy agents to myelomatargeting immune cells. There is also talk of using other recent targeted treatments in some patients who have a precursor to myeloma, in an attempt to prevent them from getting the disease.

Response rates to CAR-T cell therapy in multiple myeloma are staggering: At the 2017 annual meeting of the American Society of Hematology (ASH) in December, researchers reported that, at a median 40 weeks of follow-up, 17 of 18 evaluable patients had achieved an objective response, meaning their tumors met at least minimum shrinkage goals. That group included 10 who experienced a complete response, meaning cancer had been nearly or entirely eliminated; nine of those responded well enough to test negative for minimal residual disease: Sensitive detection techniques revealed just traces of myeloma cells in every 100,000 normal marrow cells — an amazing finding, considering that the patients in the study had undergone an average of seven prior treatments before enrolling.

For now, this groundbreaking treatment is offered only in clinical trials and primarily to patients whose disease has relapsed after many therapies. Wright, for example, tried 11 regimens, or lines, of treatment before enrolling in the CAR-T cell trial. There is a robust discussion about whether this treatment could be used in patients with earlier stages of disease, though most experts say that is at least several years away.

Multiple myeloma is a disease of plasma cells, white blood cells found in the bone marrow that, as key parts of the immune system, make antibodies. Uncontrolled growth of plasma cells can lead to anemia, fractures and bone pain, reduce the number of normal blood cells and churn out large amounts of abnormal proteins that can damage the kidneys and other organs and suppress the immune system.

Treating multiple myeloma is complex, usually involving some combination of traditional chemotherapy, nonchemotherapy drugs that target the cancer cells, corticosteroids and, in patients who can tolerate it, stem cell/bone marrow transplant. The exact combination and timing of these treatments varies from patient to patient. But even with great progress in survival duration and quality of life during the past couple of decades, multiple myeloma remains a disease without a definitive cure.

Compared with other treatments for the disease, CAR-T cells are a different animal — a living drug. The procedure adapts a patient’s immune system to fight his or her own cancer, part of a larger field called immunotherapy, which has taken the oncology world by storm. Rather than dragging a patient through months or years of therapy, CAR-T cell treatment takes just a few weeks — after which the modified T cells continue to divide in the body and fight possible relapses, providing long-term protection. The strategy offers the possibility of a durable cure to patients who previously had no options.

A REGIMEN, NOT A DRUG

CAR-T cell treatments can be described more accurately as regimens than as drugs. The technique enlists a patient’s T cells, a type of lymphocyte, or white blood cell. Lymphocytes identify and remember invading bacteria and viruses by recognizing markers on the surfaces of infectious or malignant cells. Through genetic modification, T cells are able to recognize markers associated with specific types of cancer. The marker targeted in multiple myeloma patients is called BCMA, or B-cell maturation antigen.

Doctors take a patient’s blood cells, isolate the white blood cells and use a highly modified form of HIV, the virus that causes AIDS, to insert a new coding into the gene that makes the patient’s T cells. The virus cannot transmit HIV or AIDS to patients but is an ideal delivery system for the new coding. That’s because HIV normally infects cells by inserting its own DNA, so that it can replicate. And, HIV normally infects T cells by recognizing specific receptors, leaving other cells untouched.

By inserting the new coding, the virus turns T cell receptors into a chimera, or a mixture of the patient’s genetic code and its own, all programmed to find and kill cancerous cells labeled with a particular marker, or antigen — in this case, BCMA.

The CAR-T cell regimens that were approved last year to treat leukemia and lymphoma targeted an antigen marker called CD19. The multiple myeloma studies target BCMA because it is expressed in most patients who develop the disease but usually is not expressed in non-blood cells or healthy B cells. That makes a good treatment target: The CAR-T cells kill the myeloma cells and mostly leave healthy cells alone.

To produce the live drug, T cells are removed by taking whole blood through a dialysis-like machine that spins off lymphocytes (including T cells) and returns the rest of the blood components to the patient. The collected cells are transfected (using HIV or another technique) with the gene that encodes the part of the T-cell receptor that recognizes BCMA. Then, these edited CAR-T cells are expanded in the laboratory into the hundreds of millions. Meanwhile, the patient usually is treated with chemotherapy to eradicate most of the abnormal myeloma cells, along with some normal lymphocytes, making room for the new cells.

Finally, the CAR-T cells are infused back into the patient’s circulatory system. If all goes well, they multiply into an advancing army and take out all the cancerous plasma cells by bursting their cell membranes, putting the patient into remission. The CAR-T cells can be detected in the circulation years later.

In a sense, CAR-T cell treatment combines cell therapy, gene therapy and immunotherapy in one package. Experts say it represents a radical departure from all medicines to date.

Challenges remain: CAR-T cell regimens are incredibly complicated, and each treatment costs hundreds of thousands of dollars. Researchers remain unsure how to make this a widespread, standard part of myeloma treatment.

In addition, introducing the weaponized T cells often causes a “cytokine storm,” in which many cancer cells die at once and, along with the T cells themselves, release substances that cause inflammation. This can lead to miserable flu-like symptoms, including fever, and even low blood pressure and organ damage that can be life-threatening.

The results of the 21-patient trial presented at ASH showed that 71 percent of participants experienced cytokine release syndrome, in most cases mild or moderate. In addition, 86 percent experienced serious neutropenia (a blood-count problem that can lead to infection); 57 percent, serious anemia (low red blood cell count); 43 percent, serious thrombocytopenia (low blood platelet level); and 21 percent, neurotoxicity (damage to the brain or nervous system).

BEYOND PROOF OF PRINCIPLE

Despite these drawbacks, CAR-T cell regimens are being tested in many cancer types. Studies targeting multiple myeloma are centered at the National Institutes of Health in Bethesda, Maryland; Memorial Sloan Kettering Cancer Center (MSKCC) in New York City; and the University of Pennsylvania in Philadelphia. However, many other cancer centers in the United States, Canada and Europe are collaborating in those studies and accepting patients. Researchers want to test the approach in larger numbers of patients to figure out why the engineered T cells persevere in some patients but not others. “Now there are many more trials available for the right patients,” Cohen says.

“We have proof of principle,” says C. Ola Landgren, M.D., Ph.D., chief of the myeloma service at MSK. “To my knowledge, there are now seven ongoing trials open for humans. There are differences in the details of those trials: The conditioning regimens (how patients are prepared before treatment) are different, and the patient populations and dosing are different.” A small Chinese study of just 10 patients, presented at the ASH meeting, added the CD19 target to BCMA-targeted myeloma treatment with CAR-T cells, and patients seemed to tolerate that, experts say. “The next step will be moving these treatments earlier in the disease course, to patients who’ve only had one to four prior therapies,” Cohen says. “Those patients are healthier, and their T cells are not as beat up. That’s where we are going.”

Larger studies also will explore whether other antigen targets, such as CD38 or signaling lymphocytic activation molecule F7 (SLAMF7), might be effective in treating myeloma, Cohen says. Antigens make good targets because these cancerous cells arise from lymphocytes and produce antibodies; targeted drugs that hone in on proteins are less useful in myeloma than in many solid tumor types because plasma cells do not express many known proteins.

Other efforts are linking a toxic drug to a cell that seeks out the BCMA target. Last year, an antibody-drug conjugate with the zippy name GSK2857916 was chosen by the FDA and the European Medicines Agency for quick review. In a phase 1 study of pretreated patients with few other options, the therapy yielded an overall response rate of 60 percent and durable, long responses in 51 percent of patients. Research sponsor GlaxoSmithKline is rapidly planning larger trials of the agent, both alone and paired with other therapies. “I guarantee that immunotherapies will change the multiple myeloma landscape,” says Larry Anderson, M.D., Ph.D., who treated Wright at Southwestern Medical Center. “Eventually, the majority of patients will get these treatments, and many of those patients may have long-term remissions that look like a cure.”

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