The case for CAR T cells as earlier treatment requires more evidence
The development of chimeric antigen receptor T cells has provided hope for patients with hematologic malignancies, but their commercial use has been limited to an option of last resort.
Research has intensified to maximize the effectiveness of CAR T-cell therapy, reduce toxicity and expand its use to other cancers, all while clinicians become more familiar with the modality and patients become savvier than ever about emerging treatment options from which they could benefit.
Is it too soon to consider CAR T cells as an earlier line of therapy for diseases against which it has proved effective? Could earlier deployment of this groundbreaking-yet-costly treatment lead to higher remission rates while reducing the burdens associated with multiple lengthy courses of therapy, or would doing so only balloon health care expenditures while equally effective and less-costly options exist?
“I think we have seen such strong efficacy of these CAR T cells in the treatment of advanced B-cell lymphoma, acute lymphoblastic leukemia and multiple myeloma to pose the question about how effective these cells can be when used earlier in the course of a patient’s disease — and I think the time has come to ask that question,” Stephen J. Forman, MD, director of the T-cell Therapeutics Research Laboratory in the Cellular Immunotherapy Center at City of Hope Comprehensive Cancer Center and member of the Cell Therapy Next Peer Perspective Board, told Cell Therapy Next.
“I do think the time has come to conduct studies in each of these diseases,” Forman added. “There hasn’t been enough work conducted in patients with less-advanced disease to truly make the case that CAR T cells should be used earlier, but the activity and clinical efficacy we have observed in these three diseases supports conducting trials earlier and before relapse has occurred.”
His laboratory at City of Hope is developing trials to evaluate CAR T cells as an earlier line of therapy for select patients, especially those with high-risk disease who are likely to experience progression after their initial therapy.
As the research and clinical communities await results of these studies, Cell Therapy Next asked leaders in the field to make the case for or against CAR T cells as earlier treatment for certain chronic and high-risk diseases.
Building a Case for Earlier CAR-T
The goals of moving therapy to earlier lines must be to achieve a higher cure rate and prevent disease recurrence, Forman said.
“[This] is what all cancer doctors aspire to do — to treat the disease and never have it come back,” he said.
CAR T-cell therapy currently is “an expensive proposition,” Forman said, but it could turn into a bargain over the long term if administered earlier, thereby preventing disease relapse “and all of the downstream costs that come with recurrent disease.”
The phase 2 ZUMA-12 trial is evaluating the efficacy of front-line therapy with axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead) among patients with high-risk large B-cell lymphoma. Results presented during last year’s virtual ASH Annual Meeting and Exposition showed a higher complete response rate (74% vs 58%) among treatment-naive patients than those who received CAR-T after multiple prior lines of therapy.
Although the results suggest response rates could be improved based on the timing of the therapy, they do not demonstrate CAR-T’s ability to provide superior outcomes compared with other available therapies.
The case for CAR T cells as an earlier line of therapy can only be made via randomized comparison trials, according to Robert Peter Gale, MD, PhD, FACP, FRCP, visiting professor of hematology at Imperial College London and a HemOnc Today Editorial Board Member.
“For every new therapy there comes a reckoning when convincing data are needed to prove a therapy is equivalent, safer, cheaper or hopefully better than current therapy. That hasn’t been done yet for CAR-T,” Gale told Cell Therapy Next. “That standard has not been met.”
CAR-T as earlier therapy might be feasible for certain subsets of patients, but research is lacking regarding its comparative effectiveness, Gale said. As an example, he referred to multiple myeloma — a disease cited by many of the experts Cell Therapy Next consulted as the most likely candidate for early or front-line therapy with CAR T cells.
The standard of care for a younger patient with myeloma is consolidation with autologous hematopoietic stem cell transplant after initial therapy induces remission or partial remission. Gale said although he would be willing to recommend a patient try CAR T cells in a clinical trial setting, he is uncertain about whether it is superior to autologous HSCT.
“It would have to be shown to be superior to an [autologous] transplant,” he said, adding that autologous HSCT is a fairly “benign procedure” done often as an outpatient.
“Showing you can do cell therapy safely and effectively is not adequate,” Gale said. “It has to be shown to be equivalent or better than our standard-of-care treatments.”
In addition, the rewards of moving CAR T cells into earlier lines of cancer therapy must outweigh the risks, according to Courtney Bellomo, MD, a hematologist and stem cell transplant specialist with New York Oncology Hematology, a private, community-based oncology practice in the Albany region of New York.
“If you move it to front-line therapy, you have to demonstrate that what we have already is not as good,” Bellomo, a HemOnc Today Next Gen Innovator, told Cell Therapy Next. “I do not know if that question has really been asked and answered.”
As for feasibility of providing CAR-T earlier, Bellomo said it would present a challenge for lower-income patients and those who live in rural areas, many of whom lack the time and resources to be away from home for a month or longer.
“I’m lucky and blessed that I’m in a place where we have actually delivered CAR-T as part of a research trial here in the Capital District, but a lot of community oncology practices do not have the infrastructure to deliver them,” she said.
Another issue is CAR-T’s enormous price tag, Bellomo added. Moving current CAR-T products into earlier lines of therapy likely would exacerbate socioeconomic disparities in care, she said.
The Likely Suspects
Regardless, Bellomo said she does see a future for CAR T cells as earlier therapy, especially for cancers that are treated like a chronic disease.
“I see it being really useful in the diseases where if we spend the cost upfront, it may mean you can spare people maintenance for many years, or even many years of chronic therapy,” she said.
“I believe for a disease like multiple myeloma, it will come further and further to the forefront,” Bellomo added. “I’m unsure whether it will ever be first-line therapy, but I do not think it’s going to stay as third-line and above.”
Bellomo also sees a role for earlier CAR T cells for slower-growing diseases, including chronic lymphocytic leukemia and follicular lymphoma.
For other hematologic malignancies, such as Hodgkin lymphoma — with its better than 90% cure rate using initial therapies — earlier use of CAR T cells appears unlikely, she said.
“How can you justify something that may cause harm and is really expensive?” Bellomo said. “It’s about picking the disease types where CAR-T adds a lot of benefit.”
Forman agreed and said that CAR-T as initial or earlier-line therapy could be useful for certain groups of patients.
“There are certain subgroups of adults with ALL for which it could be a consideration, maybe even instead of a stem cell transplant,” he said.
Another group includes patients with certain types of high-risk lymphoma who do not respond to initial therapy.
Patients with high-risk multiple myeloma also would be among the candidates for earlier CAR T cells, Forman said.
“These are the only types of CARs for which there has been enough experience and observation to even begin talking about it. All the other CARs are still in development,” he added.
A Disease of Interest
Last month, idecabtagene vicleucel (Abecma; Bristol Myers Squibb, bluebird bio) became the first CAR T-cell therapy to receive FDA approval for multiple myeloma.
Although the approval of idecabtagene vicleucel — also known as ide-cel — applies to adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, the success of the therapy in the pivotal phase 2 KarMMa trial has researchers wondering what they can accomplish by using this treatment earlier in the disease course.
Results of KarMMa showed a stringent compete response rate of 28% among patients who received at least three previous lines of antimyeloma therapy, and 65% of those who achieved stringent complete response remained in remission for at least 12 months.
Multiple myeloma is the disease most likely to benefit from CAR-T as an earlier line of therapy, according to Nikhil C. Munshi, MD, director of basic and correlative science within Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School.
“Currently, cures in myeloma are few and far between — many of my colleagues might say there are no cures for the disease,” Munshi, one of the primary investigators for the KarMMa trial, told Cell Therapy Next. “I personally believe that we can cure patients, but in the early phase the number of patients — if we can find a cure — will be small.”
Regardless of CAR-T’s ability to cure some patients with multiple myeloma, Munshi said the disease presents the opportunity to deploy CAR-T at an earlier and more impactful stage when it could confer superior disease control and longer remissions than currently available therapies.
CAR-T can be administered at selected localized centers and not necessarily only the largest ones, such as Dana-Farber, Munshi said. Centers with the ability to perform HSCT can easily provide CAR-T for patients with myeloma, even at earlier disease stages, he added.
“Because use of transplant is so prevalent in myeloma, switching over to CAR T cells will not be a major issue,” Munshi said. “A large part of the treatment is going to be outpatient. There is only a small part who will require inpatient stay as we move forward.”
Using CAR-T as an earlier line of therapy for patients with multiple myeloma may improve the efficacy of the treatment by using fewer pretreated T cells, according to Binod Dhakal, MD, MS, associate professor of medicine in the division of hematology at Medical College of Wisconsin and a specialist in multiple myeloma and plasma cell disorders.
Dhakal is a primary investigator for the Descartes-11 trial, which is enrolling patients with high-risk multiple myeloma. The trial will evaluate the efficacy of consolidation treatment using autologous, mRNA-engineered, B-cell maturation antigen-directed CAR T cells among patients who have residual disease after induction therapy.
So far, CAR-T has been investigated only among patients with relapsed or refractory multiple myeloma, and with impressive results, Dhakal said.
“However, more than two-thirds of patients are still experiencing disease relapse in clinical trials,” he told Cell Therapy Next.
His group hypothesizes that bringing CAR-T into front-line therapy could provide long-term disease control for patients, which could in turn provide comparable value with current therapies while improving quality of life.
“Understanding the biology of the disease and the mechanics of the CAR T cells in a relapsed or refractory setting, it comes to a point where we needed to ask: What if this effective therapy can be used very early on?” he said.
Multiple myeloma is more genetically stable, and the number of fit T cells to be harvested from patients for CAR T-cell therapy are greater earlier in the course of the disease, Dhakal said.
“Those two factors allow for the potential use of the CAR-T in a very early line of therapy and have the potential for very long-term disease control and cures in certain patients,” he said.
The Final Verdict
Nevertheless, given current limitations with the therapy, Dhakal said CAR-T must prove equal or superior to currently available treatments in randomized trials.
“We should move CAR T cells earlier and see if they fare well,” he told Cell Therapy Next. “As long as it shows the benefit is superior to the current standard of care, it is quite reasonable to bring them into an early line.”
Questions regarding cost and access will remain regardless of any trial results, Dhakal said, but the time has come to evaluate just how much benefit, if any, can be derived from using CAR-T sooner in the treatment process, he added.
“Earlier CAR-T won’t be for every patient with lymphoma, or ALL, or myeloma, but I think it will start with selected patients who look like they will need more help to overcome their disease,” Forman said.
Gale said he favors a wait-and-see approach as more evidence accumulates, but he doubts physicians would be willing to recommend CAR T cells as initial therapy when standard therapies for certain hematologic malignancies have cure rates of 80% to 90%.
“I would say the average conservative physician, rightly so, would not be willing to back off from what we currently do,” Gale said. “I’m enthusiastic about it as a scientist, but CAR-T hasn’t met the standard that normal therapies have.”
Bellomo expressed a mixed opinion. She said she is unsure whether CAR-T has a role as initial therapy but does foresee the modality being used as second-line therapy for certain diseases.
Most patients who receive CAR T cells still require subsequent hospitalization due to adverse events, “no matter what the product is,” Bellomo said.
However, she added, newer CAR-T cells in development and in clinical trials do not exhibit the same adverse-event profile. Further improvements in safety and effectiveness could add more evidence to the case for CAR T as an earlier line of therapy, Bellomo said.
“If you make CAR-T treatment a fully outpatient prospect, then it opens up the idea of being able to give it someplace rural or where the providing center does not necessarily have as much infrastructure as one finds at the big academic institutions,” she said. “If we see that kind of development, then it changes the landscape.”
- Abecma (idecabtagene vicleucel; prescribing information). Summit, NJ: Bristol Myers Squibb; 2021.
- Neelapu SS, et al. Abstract 405. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
- For more information:
- Courtney Bellomo, MD, can be reached at email@example.com.
- Binod Dhakal, MD, MS, can be reached at firstname.lastname@example.org.
- Stephen J. Forman, MD, can be reached at email@example.com.
- Robert Peter Gale, MD, PhD, FACP, FRCP, can be reached at firstname.lastname@example.org.
- Nikhil C. Munshi, MD, can be reached at email@example.com.