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 ^[1]). 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 ^[2].)

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 ^[3].