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Will CAR T cells always be reserved for late lines of therapy?
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Yes.
I am not a chimeric antigen receptor (CAR) T-cell therapy naysayer. This is a very exciting therapeutic development, both in terms of the science behind it and what it has been observed so far in initial clinical trials. However, there is still a lot we are going to have to learn before we start applying this broadly outside of highly selected clinical trials, and beyond the narrow scale in which it is currently offered.
There are several areas where we need to exercise a bit of caution in assuming that CAR T-cell therapy is going to be widely used. In many of the diseases in which it is being tested, chemotherapy continues to work relatively well in the frontline setting. For example, if we consider that the majority of patients — particularly children — diagnosed with acute lymphoblastic leukemia are going to be cured with chemotherapy, to be able to demonstrate that CAR T cells are comparable or superior to chemotherapy is going to require very large clinical trials with very long follow-up.
It stands to reason that we could see a similar trajectory for patients diagnosed with indolent lymphoma, many of whom will have low-burden disease, be asymptomatic and probably live for years with established therapies. Until we understand the prospects of long-term remission following this treatment, putting patients through a treatment regimen like that involved with CAR T cells may not be that attractive of an option. We have a lot of work to do to establish that it is effective enough to compete with the therapies we already have.
It also is important to address the practical aspects that may limit the widespread adoption of CAR T-cell therapy. With current technology, it takes a lot of effort and infrastructure to treat a patient. I assume that groups are working to make this technology more “user-friendly” from a cell production perspective, but as it stands now, it is a very labor-intensive process just to make the cells needed from an individual patient. It can regularly take around 2 weeks to treat a patient with CAR T-cell therapy; depending on the patient’s disease status — particularly at the time of presentation — they might not be able to wait that long. It is not clear to me that this is something that will ever be able to be readily done broadly at medical centers around the country.
Even if we can demonstrate that CAR T-cell therapy is superior to chemotherapy in certain malignancies, it might not be feasible that all patients will be able to receive this therapy — particularly patients who live in rural areas, away from the specialized centers where this therapy should be administered. If such a patient does not have the resources to relocate themselves for perhaps 2 months or more to receive and recover from the treatment, it will not be a plausible strategy for them. Cost also will be a huge question once it becomes available on the open market, particularly if we offer it in the frontline setting. I cannot imagine that CAR T-cell therapy will be inexpensive.
I think CAR T-cell therapy will be approved by the FDA, and it may have a huge impact on how we treat patients with certain malignancies. But I personally do not see it as a panacea across the treatment landscape of all B-cell malignancies. Until these barriers are overcome, I think our efforts should focus on offering this treatment to the most high-risk patients who are not likely to respond to standard treatments.
Ryan D. Cassaday, MD, is assistant professor of medicine at University of Washington School of Medicine and assistant member of the clinical research division at Fred Hutchinson Cancer Research Center. He can be reached at cassaday@uw.edu. Disclosure: Cassaday reports no relevant financial disclosures.
No.
There are many exciting aspects of chimeric antigen receptor (CAR) T-cell therapy. For one thing, it’s not that often that there is an entirely new form of therapy for cancer. Any new therapy generates some level of excitement.
What is really remarkable, though, is that CAR T cells can induce remissions in patients who have very high-risk disease that is refractory to other forms of targeted therapy and chemotherapy. And, it has the potential to be curative. It’s too early to say that it is curative in general, and certainly too early to predict on a per-patient basis, but it has that potential.
CAR T cells are still an investigational therapy and, therefore, can only be offered to patients who have progressed on standard therapies. But, in the future, if it continues to be this effective of a treatment, it is possible that it will move up to a much earlier line of therapy. One of the perceived challenges right now is that patients need to wait 3 or more weeks to receive their CAR T-cell products; this is likely to change in the near future for several reasons — one, there are ongoing efforts around manufacturing processes; two, the release testing that keeps many patients waiting may become more expedited; and three, treating patients earlier in their disease course will make it possible for them to schedule a slot before their disease progresses.
We hope that we will be able to identify which patients can benefit from the early use of CAR T cells. That is the goal driving a lot of the science now: engineering the best CAR T-cell products, predicting what makes a good CAR T-cell product, and predicting which patients are going to benefit from that product.
We are still in the early days of these investigations, and there are many challenges to overcome. Enrolling patients for a CAR T-cell trial is more challenging than, for example, a trial for a new targeted therapy. These diseases are more rare, often very aggressive, and the process for making the CAR T cells is extremely complex. We’re talking about getting up to a thousand patients treated, whereas for breast cancer, there are tens of thousands of patients who can be treated very quickly. Right now it is difficult to get a slot to have the CAR T cells manufactured.
Although we are not there yet, CAR T-cell therapy likely will move up to earlier lines of therapy. The possibility of liberating patients from iterative cycles of treatment is very, very appealing. Who wants to keep going to the oncologist every 3 weeks for the rest of their lives, or spend a month at a time in the hospital? For CAR T cells to move to earlier lines of therapy, though, we are going to need to improve the manufacturing process, the process of administering the cells needs to become more routine, and we need to have a better grasp on predicting which patients with which diseases are most likely to respond, and how often those responses are long-lived.
Marcela V. Maus, MD, PhD, is director of cellular immunotherapy at Massachusetts General Hospital Cancer Center and immunology faculty member at Harvard Medical School. She can be reached at mvmaus@mgh.harvard.edu. Disclosure: Maus reports that she is an inventor on some patents related to CAR T cells licensed to Novartis.