U.S. FDA Okays First Clinical Trial Of An Allogeneic CAR T-Cell Therapy For Multiple Myeloma

The U.S. Food and Drug Administration (FDA) has given the go-ahead for what is likely to be the first clinical trial of an allogeneic chimeric antigen receptor (CAR) T-cell therapy for multiple myeloma.
The potential new myeloma CAR T-cell therapy, known as UCARTCS1, is being developed by the French biopharmaceutical company Cellectis. The company announced earlier this week that the FDA approved its Investigational New Drug (IND) application for UCARTCS1 in late January.
The IND approval means Cellectis can move forward with its plans for MUNDI-01, a Phase 1 dose escalation trial of UCARTCS1. The company has not made public when the trial will start, or how many patients it will enroll, but it did say that at least three cancer centers in the U.S. will be participating in the trial: two in the New York City area, and one in Texas.
Thus far, the CAR T-cell therapies that have been tested as potential treatments for multiple myeloma have been autologous CAR T-cell therapies. Just as autologous stem cell transplants involve re-infusing patients with their own stem cells, autologous CAR T-cell therapies use genetically engineered T-cells derived from patients’ own T-cells.
Allogeneic CAR T-cell therapies, on the other hand, are derived from donor T-cells, just as allogeneic stem cell transplants make use of donor stem cells.
UCARTCS1 Not The Only Allogeneic CAR T-Cell Therapy In Development
UCARTCS1 is designed to target CS1, also known as SLAMF7, a protein frequently found on multiple myeloma cells. Empliciti (elotuzumab), a monoclonal antibody already approved in the U.S. and other countries as a treatment for multiple myeloma, also targets CS1.
In addition to UCARTCS1, there are several other allogeneic CAR T-cell therapies being developed as potential multiple myeloma treatments. These include ALLO‑715 from Allogene Therapeutics, P‑BCMA‑ALLO1 from Poseida Therapeutics, and CTX120 from CRISPR Therapeutics.
All three of these other allogeneic therapies target the B-cell maturation antigen, or BCMA, which also is the target of the best known autologous CAR T-cell therapies under development as myeloma treatments, including bb2121 and JNJ‑68284528 (LCAR‑B38M).
Although UCARTCS1 is likely to be the first allogeneic CAR T-cell therapy tested in a clinical trial, the other allogeneic therapies are not far behind. Allogene also intends to start a Phase 1 trial of ALLO‑715 this year, and Poseida is targeting late this year or early next year for the first trial of P‑BCMA‑ALLO1.
Potential Significance Of Allogeneic Therapy
Although allogeneic CAR T-cell therapies and allogeneic stem cell transplant both rely on donor cells, they differ in an important way. Allogeneic CAR T-cell therapies should be able to be used more extensively than allogeneic stem cell transplants because they will not require the sort of donor-recipient tissue matching necessary for allogeneic stem cell transplants. This tissue matching is necessary with allogeneic stem cell transplants to reduce the chances of graft versus host disease, the potentially life threatening complication that occurs when a patient’s immune system rejects donated stem cells.
With allogeneic CAR T-cell therapies, the chances of graft versus host disease are minimized by design. Some of the genetic modifications donated T-cells undergo as they are transformed into allogeneic CAR T-cell therapies are carried out because they prevent the altered T-cells from being rejected by a patient’s immune system.
Because tissue matching will not be necessary for allogeneic CAR T-cell therapies, the treatments will be able to be produced regularly and at a large scale. This means allogeneic CAR T-cell therapies are likely to have two key advantages versus autologous CAR T-cell therapies:
- Availability – If a doctor decides a patient needs treatment with an allogeneic CAR T-cell therapy, the patient will be able to be treated almost immediately. This is why allogeneic CAR T-cell therapies sometimes are called “off-the-shelf” CAR T-cell therapies. With autologous CAR T-cell therapies, treatment cannot begin until a patient’s T-cells are harvested, sent off for processing, modified, and then returned for infusion.
- Cost of production – Production of an allogeneic CAR T-cell therapy will be able to be carried out on a large scale rather than the individual, batch-by-batch basis necessary for autologous CAR T-cell therapies. It also may be easier with allogeneic therapies to locate production in parts of the world where labor, equipment, and laboratory space are less expensive. At least one study suggests allogeneic CAR T-cell therapies may be as much as 95 percent less expensive to produce as autologous CAR T-cell therapies (Harrison et al., Cytotherapy, 2019). If this is true, and if lower production costs lead to lower prices for allogeneic CAR T-cell therapies, doctors and healthcare systems may be more willing to use them in a broader array of patients, and to employ more than a single CAR T-cell therapy dose per patient (as typically has been the case thus far with CAR T-cell therapies).
It remains to be seen, however, whether allogeneic CAR T-cell therapies will be as potent as autologous CAR T-cell therapies. Proponents of the allogeneic therapies argue that, because they are derived from the cells of healthy donors, they have the potential to be more effective than comparable autologous therapies. Clinical trial results do not yet suggest that this will be the case.
For example, early results for UCART19, an allogeneic CAR T-cell therapy being tested as a potential new treatment for acute lymphoblastic leukemia (ALL), do not indicate it is clearly more effective than Kymriah (tisagenlecleucel), a comparable autologous CAR T-cell therapy already approved by the FDA as a treatment for ALL. Both UCART19 and Kymriah target CD19, a protein frequently found on the cancer cells prevalent in patients with ALL. (Kymriah, which initially was known as CTL019, also has been tested in patients with multiple myeloma.)
Does Allogeneic Equal Curative?
When people with multiple myeloma hear the word “allogeneic,” they not only think “donor”; they also think “potentially curative.” This is because allogeneic stem cell transplants, particularly when carried out in patients who have achieved a deep response to induction therapy, can be a cure for some multiple myeloma patients.
This does not mean, however, that allogeneic CAR T-cell therapies can be expected to have the same curative potential. Allogeneic stem cell transplants involve replacing most of a patient’s immune system with the immune system of a healthy donor. Stem cells are much more than T-cells, the type of white blood cell utilized in CAR T-cell therapy. Stem cells are the source of every kind of blood cell, including T-cells, natural killer cells, and all the other types of blood cells involved in the body's defense against cancer and other diseases.
As a result, while allogeneic CAR T-cell therapies may turn out to be curative in some patients, it most likely will be for reasons other than the fact that the therapies are allogeneic (i.e., donor derived).
More About The UCARTCS1 Trial
For additional information about the FDA approval of the UCARTCS1 clinical trial, see the related press release from Cellectis.
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