Early Results with Allo-CAR-T Products Allo-715 and Allo-647

Many interesting presentations were given at the most recent ‘virtual’ multi-day conference of the American Society of Hematology (ASH) discussing progress with a variety of CAR-T programs that target multiple myeloma. One of those covered the Allogene company’s products Allo-715 and Allo-647. The names already imply that we are dealing here with ‘off the shelf’ CAR-T products. Much of what the Myeloma Crowd has published in the past has focused on ‘standard’ CAR-T products where a patient’s T-cells are harvested, genetically modified into CAR-T cells, expanded into large quantities to step up their cancer killing power and then infused back into the patient. This process can take up to three weeks, a period where patients continue to deteriorate physically which may impact to future efficacy of the CAR-T infusion. 

A recent article published on our website introduced the concept of ‘off the shelf’ CAR-T. The need for such a product is clear: it allows for immediate treatment of a patient without having to wait for the potentially life-saving CAR-T cells. These healthy-donor CAR-T cells also solve the problem of variable quality of the patient’s T-cells with resultant variable quality of CAR-T cells (and resultant variable quality of the treatment). These donor derived cells are, in essence, an allogeneic transplant (hence the name allo-CAR-T) and therefore come with the luggage that some of us are already familiar with: Graft-versus-host-Disease (GvHD). This occurs when the body starts to attack the foreign invader cells, leading to a miserable experience for the patient. The objective, therefore, for any allo-CAR-T product is to have a patient centric process that obviates or minimizes the incidence rate and the severity of GvHD.

This brings us back to Allogene’s products mentioned earlier. Remember though that, just as with a regular Stem Cell Transplant that most of us are familiar with, CAR-T treatment also requires a conditioning or lymphodepletion step where the patient is infused with a cancer killing product (typically melphalan for auto stem cell transplant) to kill as many of the cancerous cells as possible prior to infusion of stem cells or, in this case, CAR-T cells. The Company has developed a two-step and two-product therapy that, hopefully, will turn out well for us multiple myeloma patients. The two steps/products are:

• ALLO-647 a monoclonal antibody that targets the surface protein CD-52 for selective and prolonged host lymphodepletion (LD)
• ALLO-715 a genetically modified, donor cell derived, anti-BCMA Allo-CAR T cell product in which one specific gene is disrupted to reduce the risk of graft-versus-host disease (GvHD)

The Company and its collaborators presented results of a Phase I study with myeloma patients whose disease had relapsed after at least 3 prior treatments that included proteasome inhibitors, immunomodulators as well as monoclonal antibodies that target the myeloma surface cell protein CD-38. In other words, the very sickest of our fellow patients. The aim of Phase I studies is to determine dose levels that are safe and effective for future patients.  Multiple dosing regimens need to be tried to determine what is expected to work best for a patient while still be safe. The fact that two different products are involved here means that the Company had to develop a complex dose ranging program with multiple different combinations of lymphodepletion/CAR-T doses.

ASH published the outcomes of the small 15-patient study. Critical to know here is that no neurotoxicity nor GvHD events were noted in any of the different combinations administered, though the depth of response against myeloma was more pronounced with higher cell doses of Allo-715 (which was somewhat expected). Other key results are: 

• In patients who received dose level 3 and conditioning program FCA, 2/3 responded (1 Stringent Complete Response and 1 Very Good Partial Response) 
• All dose level 3 patients who responded experienced at least a Very Good Partial Response and achieved MRD negative status by local MRD testing. All responses were initially observed at day 14.

In other words, these results may be very early, but they already are quite exciting in that they show progress with an allo-CAR-T product to treat multiple myeloma with an acceptable safety and efficacy profile. All of this combined may become a major potential treatment option for us in the future (assuming that further clinical studies will confirm positive results) and give us continued hope. I have simplified the outcomes of this early study and I encourage those who would like to know more detail about the study design to refer to the link highlighted above for the full detail. It is only a 5-10 minute (interesting) read.

The Company is still recruiting patients to round out a 90-patient study pool. Information regarding this study, including contacts and study sites, can be found here.