Excitement is growing for the treatment of patients with various forms of cancer using? immunotherapy ? specific therapies that harness the power of a patient?s own immune system to combat their disease.
The concept involves engineering chimeric antigen receptor T cells, also known as natural killer cells, for a specific antigen that is more prevalent in a specific disease sub-type and then utilize those T cells to recognize cancer cells with CAR specific cell surface proteins and induce long-term remissions in patients with a specif cancer or hematologic malignancy.
In an early clinical trial funded by Legend Biotech Co, 33 out of 35 (94%) of participating patients had clinical remission of multiple myeloma upon receiving a new type of immunotherapy ? chimeric antigen receptor (CAR) T cells targeting B-cell maturation protein or BCMA. Most patients had only mild side effects. [1]
The study was presented at the 53rd annual meeting of the American Society of Clinical Oncology (ASCO), held Jun2 2 – 6, 2017 in Chicago, Ill.
Multiple myeloma is a cancer of plasma cells, which make antibodies to fight infections. Abnormal plasma cells can crowd out or suppress the growth of other cells in the bone marrow. This suppression may result in anemia, excessive bleeding, and a decreased ability to fight infection.
Multiple myeloma is a relatively uncommon cancer. But according to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI), an estimated 30,300 people [1] will be diagnosed this year in the United States with multiple myeloma, while 12,600 are expected to die of the disease. Only about half (49.6%) of patients survive five years after being diagnosed with the disease.[2]
Worldwide, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015, representing a net increase from only 49,000 in 1990! [3][4][5]
Photo 1.0: Wanhong Zhao, MD, Ph. D, associate director of hematology at The Second Affiliated Hospital of Xi?an Jiaotong University in Xi?an, China, presenting Abstract LBA3001, Durable remissions with BCMA specific chimeric antigen receptor (CAR)-modified T cells in patients with refractory/relapsed multiple myeloma, at the American Society of Clinical Oncology (ASCO).Advances
?Although recent advances in chemotherapy have prolonged life expectancy in multiple myeloma, this cancer remains incurable,? said study author Wanhong Zhao, MD, PhD, an associate director of hematology at The Second Affiliated Hospital of Xi?an Jiaotong University in Xi?an, China.
?It appears that with this novel immunotherapy there may be a chance for cure in multiple myeloma, but we will need to follow patients much longer to confirm that,? Zhao added.
Custom-made therapy
CAR T-cell therapy is ‘custom-made’for each patient. The patient?s own T cells are collected, genetically reprogrammed in a lab, and injected back into the patient. The reprogramming involves inserting an artificially designed gene into the T-cell genome, which helps the genetically reprogrammed cells find and destroy cancer cells throughout the body.
Over the past few years, CAR T-cell therapy targeting a B-cell biomarker called CD19 proved very effective in initial trials for acute lymphoblastic leukemia (ALL) and some types of lymphoma, but until now, there has been little success with CAR T-cell therapies targeting other biomarkers in other types of cancer. This is one of the first clinical trials of CAR T cells targeting BCMA, which was discovered to play a role in progression of multiple myeloma in 2004.
Key Findings
The authors report results from the first 35 patients with relapsed or treatment-resistant (refractory) multiple myeloma enrolled in this ongoing phase I clinical trial in China. First signs of treatment efficacy appeared as early as 10 days after initial injection of CAR T cells (patients received three split doses of cells over a week). Overall, the objective response rate was 100%, and 33 (94%) patients had an evident clinical remission of myeloma (complete response or very good partial response) within two months of receiving CAR T cells.
To date, 19 patients have been followed for more than four months, a pre-set time for full efficacy assessment by the International Myeloma Working Group (IMWG) consensus. Of the 19 patients, 14 have reached stringent complete response (sCR) criteria, one patient has reached partial response, and four patients have achieved very good partial remission (VgPR) criteria in efficacy.
There has been only a single case of disease progression from VgPR. An extramedullary lesion of the VgPR patient reappeared three months after disappearing on CT scans. There has not been a single case of relapse among patients who reached sCR criteria. The five patients who have been followed for over a year (12-14 months) all remain in sCR status and are free of minimal residual disease as well (have no detectable cancer cells in the bone marrow).
Cytokine release syndrome
Treatment with CAR T-cell therapy may cause several undesirable and potentially dangerous side effects. Cytokine-release syndrome or CRS is among the most common, severe and troublesome side effect of CAR T-cell therapy.
CRS occurs when infused T cells release cytokines, which are chemical messengers that help the T cells carry out their duties. However, with cytokine-release syndrome, there is a rapid and massive release of cytokines into the bloodstream.? This can cause dangerously high fevers and precipitous drops in blood pressure. CRS is also associated with symptoms such as difficulty breathing, and problems with multiple organs.
In this trial CRS occurred in 85% of patients. However, the researchers report that it was only transient. In the majority of patients symptoms were mild and manageable.
Only two patients experienced severe CRS (grade 3) but recovered upon receiving tocilizumab (Actemra?, Genentech) an inflammation-reducing treatment commonly used to manage CRS in clinical trials of CAR T-cell therapy. No patients experienced neurologic side effects, another common and serious complication from CAR T-cell therapy.
Expert opinion
“While it?s still early, these data are a strong sign that CAR T-cell therapy can send multiple myeloma into remission,” said Michael S. Sabel, MD, FACS, ASCO Expert who was not involved in this study.
“It?s rare to see such high response rates, especially for a hard-to-treat cancer. This serves as proof that immunotherapy and precision medicine research pays off. We hope that future research builds on this success in multiple myeloma and other cancers,” Sabel added.
His views are similar to those expressed by other experts, including? Steven A. Rosenberg, MD, Ph.D, Senior Investigator, Head, Tumor Immunology Section, Center for Cancer Research at the National Cancer Institute in Bethesda, MD.
Rosenberg who pioneered the development of effective immunotherapies and gene therapies for patients with advanced cancers, including the adoptive transfer of genetically modified lymphocytes have resulted in the regression of metastatic cancer in patients with a variety of cancers and hematological disorders, noted in an article published in Nature Reviews, that “CAR T-cell therapy [may] eventually […] become a standard therapy for some […] malignancies.”
What’s Next
The researchers plan to enroll a total of 100 patients in this clinical trial, at four participating hospitals in China.
?In early 2018 we also plan to launch a similar clinical trial in the United States. Looking ahead, we would also like to explore whether BCMA CAR T-cell therapy benefits patients who are newly diagnosed with multiple myeloma,? Zhao concluded.
Last editorial review: June 7, 2017
Featured Image: Attendees during the day at the American Society of Clinical Oncology (ASCO) Annual Meeting, Friday June 2, 2017.?Courtesy: ? 2017 ASCO/Scott Morgan. Used with permission. Photo 1.0: Wanhong Zhao, MD, Ph.D. Courtesy: ? 2017 ASCO/Scott Morgan. Used with permission.
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