The remarkable results in leukemia patients treated with chimeric antigen receptor (CAR)-modified T-cells, which have caused such excitement among specialists treating hematologic malignancies, are now being published.
In some cases, this approach to therapy, which is personalized for each patient, has been shown to "eradicate" the disease, say investigators.
Two groups are at the forefront of this treatment approach — one based at the National Cancer Institute (NCI) and the other based in Philadelphia. Both presented early clinical results in December 2013 at the annual meeting of the American Society of Hematology.
Now, the NCI researchers, led by Daniel Lee, MD, report results from a phase 1 trial conducted in 21 children and young adults with relapsed or refractory acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma in a study published online October 13 in the Lancet.
The team from the Children's Hospital of Philadelphia and the University of Pennsylvania are due to publish their clinical results later this week. This group has teamed up with Novartis to commercialize the therapy.
Both teams are using CAR-modified T-cells that target CD19, but use different technologies (the NCI team uses retroviral-vector technology, while the Philadelphia team use lentiviral-vector technology).
The treatment involves a single autologous T-cell infusion.
Each patient undergoes leukapheresis to obtain peripheral blood mononuclear cells. T-cells are removed, modified, and then incubated for several days in order to grow enough of the CAR-modified T-cells to produce a therapeutic dose (which has been achieved in most, but not all, patients). These modified T-cells are then infused back into the patient, under close monitoring, as they can provoke a cytokine-release syndrome, and some patients have needed intensive care.
The results seen with the therapy have been dramatic.
Among the series of 21 young patients reported by the NCI researchers, there were six patients with primary chemorefractory ALL who had never achieved a remission despite many intensive chemotherapy regimens.
After one infusion of CAR T-cell therapy, all six patients had a complete response, which "provides evidence that this therapy can eradicate chemoresistant leukemia," the authors write.
Overall, 14 of the 21 patients in the study (70%) had a complete response, and 12 of these patients (60%) had no evidence of disease when measured with a highly sensitive technique that establishes minimal residual disease (MRD)-negative complete response.
These complete response rates are "substantially higher" than those reported with the most recent US Food and Drug Administration (FDA)-approved agent for refractory pediatric ALL, the researchers note. They are referring to clofarabine (Clolar), approved in 2004, which has published complete response rates ranging from 8% to 20%.
In addition, the NCI researchers highlight the responses seen in two patients who had had measurable central nervous system (CNS) leukemia when enrolled into the study, which then "disappeared" at the same time that the modified T-cells were seen in the cerebrospinal fluid (CSF). "This work provides the first evidence that CD19 CAR T-cells can eradicate leukemia in CSF," they write, and this raises the prospect that this therapy could prevent or treat CNS leukemia without long-term toxicity, they add.
A Bridge to Stem Cell Transplant
The standard of care for refractory patients with B-ALL who achieve MRD-negative remission is to proceed to hematopoietic stem cell transplantation (HSCT) when medically eligible, the researchers note.
Hence, 10 of 12 patients who became MRD-negative in their trial went on to HSCT, and all remain disease-free (median follow-up, 10 months).
The other two patients were judged ineligible for HSCT by their treating physicians. Both have since relapsed with CD19-negative leukemia, at 3 and 5 months, respectively. One of these patients went on to receive a second infusion of CAR-modified T-cells but had no objective response.
"We conclude that CD19-CAR T-cell therapy is an effective bridge to HSCT in patients with chemorefractory B-ALL," they write.
Because most of the patients who entered remission went on to receive a HSCT, this study cannot assess the durability of the response to CD19-CAR, they note.
The therapy was associated with a favorable long-term survival in this study, the researchers note. Overall survival was 51.6% at 9.7 months and beyond (median follow-up, 10 months).
Toxicity Was Reversible
All toxicities associated with the therapy were reversible, Dr. Lee and colleagues comment.
The most common and severe adverse event was cytokine-release syndrome, which was grade 4 in three patients (14%) and grade 3 in three patients (14%). One of these patients had a cardiac arrest but was successfully resuscitated. Reversible neurotoxicity was seen in six patients, and included visual hallucinations (in five patients) and transient dysphasia (one patient).
This syndrome is associated with raised levels of interleukin (IL)-6, and the researchers note that it can be reversed with the anti-IL-6 receptor antibody tocilizumab (RoActemra), which is already marketed for rheumatoid arthritis. During the trial, the team used tocilizumab both with and without corticosteroids, but they propose that going forward the drug should be used alone as a first-line agent for severe cytokine-release syndrome, as it rapidly reverses the syndrome, and they worry that high-dose corticosteroids might ablate the CAR T-cells.
The most common nonhematologic grade 3 adverse events were fever (43% of patients), hypokalemia (43%), and fever and neutropenia (38%).
Unsuccessful in Some Patients
In this study, enough modified T-cells for treatment were generated in 19 of 21 patients.
The researchers speculate as to why the therapy was not effective in all patients. One patient had inadequate T-cell function, probably as a result of clofarabine-based therapy just a month before leukapheresis, and two other patients had an overwhelming disease burden.
Two further patients had loss of CD19 antigen expression, which the researchers described as "an Achilles heel of CD19-directed therapies for B-ALL." To get around this, they have created a new CAR-modified T-cell that targets another antigen, CD22, and say that in the future it may be possible to use a bivalent CAR targeting both CD19 and CD22 to "prevent escape due to antigen loss."
The researchers also hint that less of a response appears to have been seen in patients who had already undergone a HSCT prior to enrolling in the study (this was the case for 8 of the 21 participants), although they also caution the numbers involved are small and the study is not powered to detect a difference, the researchers note. Nevertheless, they state that an MRD-negative complete response was seen in three of seven (43%) patients who had undergone HSCT prior to the study, compared with nine of 13 patients (69%) who had not.
The current results show that the therapy is feasible and yields a high response rate after one infusion of cells, manufactured within 11 days, the NCI researchers conclude.
Pharma Companies Getting Involved
The NCI has a collaboration with Kite Pharmaceuticals to develop CD19 CAR T-cell therapy, and has also seen promising results with this approach in the treatment of aggressive non-Hodgkin's lymphoma.
Another group working on this novel approach to treatment is Juno Therapeutics, which is working on CAR technology with three large cancer institutions: the Fred Hutchinson Cancer Research Center in Seattle, the Memorial Sloan Kettering Cancer Center in New York City, and Seattle Children's Research Institute.
Other companies involved in this field include Pfizer (working with Cellectis SA, France), and Celegene (working in collaboration with Bluebird Bio Inc.), according to an article in the Wall Street Journal. "Competition will keep all of these companies on their toes," one company executive told the newspaper.
The challenge with this therapy, which is made individually for each patient, is to get the manufacturing process to "a viable level where it's both affordable and attractive," another executive says. The article notes that while most biotech analysts say it is too early to speculate on the cost of such a therapy, one group has suggested a price of more than $500,000 per patient, which is roughly in line with the cost of stem cell transplant. But the potential is a cure, several company executives point out.
"I think a cure for cancers such as leukemia and lymphoma through a CAR technology is plausible," says Usman Azam, head of cell and gene therapies at Novartis. "Our job is to get this into patients as soon as we feasibly can."
Novartis is working with the Philadelphia group, and its lead product, CTL019, an investigational CAR therapy for the relapsed/refractory ALL, has been granted breakthrough status by the FDA.
The Wall Street Journal article also quotes Daniel DeAngelo, MD, PhD, associate professor at Harvard Medical School and the Dana-Farber Cancer Institute in Boston, who has not been involved in any of the studies, as saying: "CAR T-cells are probably one of the most exciting concepts and field to come out of cancer in a very, very long time."
The NCI researchers have disclosed no relevant financial relationships.
Lancet. Published online October 13, 2014. Abstract
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Cite this: CARs Motor Through Leukemia, Can 'Eradicate' Disease - Medscape - Oct 13, 2014.