Allogene’s Off-the-Shelf Myeloma CAR-T Data Marred by Patient Death

 

South San Francisco-based Allogene Therapeutics released some early data from its Phase I UNIVERSAL clinical trial of ALLO-715 for relapsed/refractory multiple myeloma. The company plans to present data in December at the 62^ndAnnual Meeting of the American Society of Hematology (ASH). ALLO-715 is the company’s allogeneic, in other words, off-the-shelf, CAR T (AlloCAR T™) therapy for a variety of cancers.

Traditional, autologous CAR T involves taking blood from a cancer patient, isolating white blood cells, engineering the immune cells to specifically attack the patient’s cancer and reinfusing them into the patient. With off-the-shelf or allogeneic CAR T, the white blood cells being infused are not unique to the patient, but have been collected from donors and engineered to attack more universal molecules on the patient’s cancer cells.

The data Allogene released shows promise, but was shadowed by the death of one patient. The data presented so far is on the first 15 patients that were evaluable for efficacy and received escalating doses of ALLO-715 in addition to a lower dose of ALLO-647. All the patients had advanced disease and had received a median of five previous lines of therapy.

In the 15 patients, higher doses of ALLO-715 demonstrated more activity, with 60% of the patients (three out of five) responding. Of the three patients who received that dose, two responded, one with a stringent complete response (sCR) and one very good partial response (VGPR). Both were minimum residual disease (MRD) negative by local MRD testing.

At the time of the data cutoff, 17 patients could be evaluated for safety. There were no signs of neurotoxicity or graft-vs-host disease. Four patients demonstrated cytokine release syndrome (CRS) with three Grade 1 and one Grade 2. All were resolved without use of corticosteroids or tocilizumab. The most common Grade 3 adverse events were anemia, neutropenia, lymphopenia and thrombocytopenia.

However, four cases of Grade 3 or greater infections were seen. Three were Grade 3 and were successfully treated. The fourth was a Grade 5 of what they believe was fungal pneumonia that occurred on the eighth day after ALLO-715 infusion. The pneumonia was diagnosed on the day after cell infusion and the patient, after receiving multiple lines of therapy, died. The investigator concluded the death was related to progressive disease and the conditioning regimen.

In a note to investors, Biren Amin, analyst with Jefferies, wrote that infections are relatively common in patients receiving anti-BCMA CAR T therapy—in a separate ASH abstract, about half of patients receiving this form of therapy had infections, largely because the immune system is depleted as part of the conditioning regimen, making patients more susceptible to infections prior to the treatment.

Despite the success in two of the patients, Cory Kasimov, an analyst with JPMorgan, wrote in a note to clients, “Although early, the efficacy looks underwhelming when compared to autologous CAR T therapies. These are the traditional CAR T that use a patient’s own cells instead of off-the-shelf donor cells. “[The] Grade 5 death due to infection related to lymphodepletion is concerning.”

There are two other CAR T therapies, at least, in development for multiple myeloma. Bristol Myers Squibb is developing one with bluebird bio, which is currently being reviewed by the U.S. Food and Drug Administration (FDA). Johnson & Johnson licensed another from Legend Biotech, and it has shown promise in the clinic.

Although autologous CAR T is generally very effective, it is expensive and time consuming. Which is why there is so much focus on allogeneic, off-the-shelf products. They are encouraging, but it’s still undetermined if they are as effective and as durable as the autologous therapies and whether a patient’s immune system will reject the allogeneic, off-the-shelf products.

Rafael Amado, executive vice president of Research & Development and chief medical officer of Allogene, stated, “We’re looking forward to presenting initial clinical data for our first anti-BCMA AlloCAR T therapy, ALLO-715, which we believe will provide insights into how we might optimize lymphodepletion and cell dose to reach its potential for patients in need of readily available treatment options. These findings will help inform trial design for our BCMA platform as we look to advance ALLO-715, alone and in combination with a gamma secretase inhibitor, as well as ALLO-605, our first TurboCAR T clinical candidate.”