Autologous vs. allogeneic CAR-T: Decisions must be made ‘carefully and deliberately’
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Allogeneic or “off-the-shelf” chimeric antigen receptor T-cell therapies have moved into early-phase clinical testing with the hope that they will offer many advantages over autologous regimens.
In this installment of In Practice, Marcela V. Maus, MD, PhD — director of the cellular immunotherapy program at Massachusetts General Hospital, assistant professor of medicine at Harvard Medical School and member of the Cell Therapy Next Peer Perspective Board — discussed the rapidly expanding research into allogeneic CAR T-cell therapy.
Question: Are allogeneic CAR T-cell therapies available only via clinical trials?
Right now, yes. There are three FDA-approved autologous CAR T-cell products, but there are no allogeneic CAR T-cell products on the market.
Q: How do you help patients select the therapy that best fits their disease if cell therapy is the modality of choice?
It depends on the patient’s disease type. Currently, the standard of care would be the approved autologous T-cell products. When it comes to choosing among the available allogeneic therapies being tested in clinical trials, it depends on a confluence of factors, including the patient’s eligibility, whether the patient has received previous autologous CAR T cells, how quickly they need a manufactured product and whether there is a slot available in the clinical trial.
Q: How would you characterize the current state of development of allogeneic CAR T-cell therapies?
It is moving very quickly, but it is still early. For example, only one allogeneic therapy was reported on during ASCO20 Virtual Scientific Program, and that was the data from Allogene. Overall, allogeneic therapies are at the very early stage of development.
Q: What is the state of development of autologous CAR T-cell therapies?
We already have approved therapies in the autologous space, including for B-cell lymphoma, leukemia and mantle cell lymphoma. These are now a part of the standard of care. We are in late-stage development of autologous CAR-T for multiple myeloma.
Q: What are the perceived benefits of allogeneic vs. autologous therapies?
The major perceived benefit is that the product will be more quickly available for the patient. Because it is an off-the-shelf therapy, the patient would not have to wait for it to be manufactured.
Another benefit to both industry and the patient is the perception that allogeneic CAR-T products will be less expensive. Data supporting these assumptions have yet to be borne out. It remains to be seen whether any cost savings associated with allogeneic therapies will be shared by both the patient and the manufacturer.
Finally, another benefit may arise for patients with certain diseases — or those who have undergone treatment with certain types of therapy — that impact the quality of their immune system and their T cells. There is a perception that starting with healthy T cells could make the therapy more potent.
Q: What are the perceived benefits of autologous vs. allogeneic therapies?
Because an autologous therapy is derived from the patient’s own cells, it reduces the likelihood that the patient’s immune system will attack those cells. There is something both psychologically and biologically valuable to autologous therapies being derived from the patient’s immune system. It also allows us to avoid having to use powerful anti-rejection medications that further suppress the immune system.
Q: What are some of the risks associated with allogeneic therapies?
First, they require that we give the patient powerful drugs to help avoid rejection of the new cells, just like when having an organ transplant. They are very powerful immune suppressants, and managing these therapies is a challenge in that the dosing regimens need adjustments — often more than once a week. This requires a high level of interaction between the patient and the health care team.
When a patient’s immune system is suppressed, they are far more susceptible to infection. This constant immunosuppression leads to use of more medications to prevent infection. If a patient develops an infection, they are at a much higher risk for developing a severe infection.
Another challenge of allogeneic therapies is that they can include the need for gene-editing technologies, such as CRISPR and TALEN. This is an exciting scientific development, but it doesn't have a long track record in humans to establish its safety. By altering the genome, there is the possibility of long-term secondary malignancies or off-target effects. It adds another layer of risk that we don’t yet know how to fully evaluate.
Q: Does either approach have greater potential for treating solid tumors?
The issue with solid tumors is not what cell type you use to treat it. Rather, the questions are: Do the cells have a target to locate solid tumor cells, will a cellular therapy be resistant to the tumor microenvironment, and would it be safe in that it recognizes normal tissue with a similar profile? We face these issues regardless of whether it is an allogeneic or autologous cell product.
If studies looking to use allogeneic cell therapies to treat solid tumors are successful, they would be transformative. However, I think it will take a while to achieve this goal.
Q: What are the key challenges to developing effective allogeneic CAR T-cell therapies?
Issues involve the manufacturing processes, such as the genome editing that may be required and procurement of a large enough quantity of certain cell types — including cord blood, natural killer cells or gamma-delta T cells. Another issue is manipulating the host and cell interaction to influence the rejection direction and graft-versus-host disease direction. These issues are being addressed by therapies in development.
Q: Could patients who are unable to have autologous cell therapies manufactured from their own cells benefit from an allogeneic therapy?
Yes. This is one of the biggest hopes among those who develop these therapies. If a patient has low-quality T cells — for any number of reasons — and they still have time to seek another treatment, it's a good reason to try an allogeneic product.
Q: Are there any decision-making algorithms or clinical guidelines that you follow when presenting patients with treatment options?
Each patient is different, so we discuss patients as a group, either in a disease group or in the cell therapy group. We discuss the potential therapies, including what therapy may be next. We don’t limit the discussion to which cell therapy is best. We also consider what other trials and drugs are available for a particular patient.
Q: Are there specific disease types that are more promising for treatment with allogeneic CAR T-cell therapies?
We don't really know the answer to this yet.
Q: Is there anything else you want clinicians to know about choosing between autologous and allogeneic cell therapies?
Right now, it’s a bit of a false choice. There are a limited number of centers that have allogeneic CAR T-cell clinical protocols open, whereas autologous CAR T cells are widely available. So, the decision needs to be made carefully and deliberately. As with any clinical trial, considering what’s best for an individual patient along their disease journey is important.
For more information:
Marcela V. Maus, MD, PhD, can be reached at Massachusetts General Hospital, 149 13th St., Room 3.216, Charlestown, MA 02129; email: mvmaus@mgh.harvard.edu.
To contribute to In Practice or to suggest topics, email us at CellTherapyNext@healio.com.
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