“This is just a different way of achieving TCR knockdown and probably enabled them to generate intellectual property,” said Dr Atanackovic. “I cannot think of any major clinically relevant advantages or drawbacks [to this approach]. That is the only component that is innovative and new, at least to a certain degree. The target BCMA and allogeneic approaches in general have been used before,” he added.
Removal of the endogenous TCR is vital for the prevention of graft-vs-host disease (GVHD) and because the shRNA approach has not been tested yet in these types of therapies in human trials, it remains to be seen whether the TCR will be adequately suppressed.
“We will have to see what happens with CD3 zeta; we don’t have many trials to see what happens with this and we will need to see what the side effects are and whether this shRNA approach works, although it seems viable,” said Dr Madduri.
CAR T cells have been set back by numerous side effects from their first trials in children with relapsed leukemia, where cytokine release syndrome (CRS) resulted in some early fatalities.
“Allogeneic approaches are typically associated with graft-vs-host responses and, more generally, more severe immune reactions including CRS,” said Dr Atanackovic. CRS is now considered largely manageable due to the use of IL-6 inhibitors such as tocilizumab, but neurotoxicity with CAR T cells, generally, and GVHD with allogeneic approaches are considerable concerns.
“The biggest thing to watch out for is GVHD; the second thing is the CRS and neurotoxicity. People think that myeloma CARs have a lot of toxicity, but they are actually well-tolerated compared to the lymphoma CARs. We normally see grade 1 and 2 CRS, but I think the biggest one for off-the-shelf CARs is aggravating GVHD,” said Dr Madduri.
As well as these side effects, in early July 2020, a Cellectis trial (ClinicalTrials.gov Identifier: NCT04142619) using allogeneic CAR T cells targeting CS1 in multiple myeloma was put on hold by the FDA after a patient on the trial experienced a fatal cardiac arrest.
“Unfortunately, we recently had deaths using allogeneic CAR T cells targeting CS1 in myeloma. I would be somewhat hesitant at the moment to pursue allogeneic approaches without more information on the deaths that recently occurred,” said Dr Atanackovic.
In addition, more than two-thirds of multiple myeloma patients in a clinical trial (ClinicalTrials.gov Identifier: NCT04142619) with GlaxoSmithKline’s BCMA-targeting antibody-drug conjugate belantamab fadotin experienced eyesight problems related to the cornea, with just under half experiencing at least 1 severe issue.
Celyad plans to start the dose-escalation phase 1 trial of CYAD-211 by the end of 2020 and will be enrolling patients with relapsed/refractory multiple myeloma.
Disclosure: Dr Madduri disclosed financial ties with the pharmaceutical industry.
Editor’s note: This article was updated on 9/9 to correct CD37 to CD3 zeta and to clarify a company name.