A distinctive feature of CAR T therapy is that it is individually designed. Each patient receives a unique cancer-fighting infusion made from their own immune cells. The crucial process of genetically modifying the cells, however, is long and expensive. Early study results from the UNIVERSAL clinical trial evaluate a promising solution: a ready-made version of CAR T therapy for multiple myeloma. The treatment shows encouraging safety and efficacy profiles, bringing the commercialized CAR T therapy concept one step closer to clinical translation.
Multiple myeloma and CAR T therapy
Multiple myeloma (MM) is a cancer of the plasma cells of the bone marrow. This cancer initially responds well to chemotherapy, targeted therapy, and other first-line therapies. Unfortunately, the disease often returns and becomes resistant to previous treatments. When other options are no longer effective, CAR T cells can achieve a lasting response.
There are currently two FDA-approved CAR T-cell products for multiple myeloma: Ide-cel and cilta-cel. Ide-cel impressively reduces signs of multiple myeloma in 72% of patients, and cilta-cel in 98% of patients. Both require the extraction and modification of the patient’s cells to target B-cell maturation antigen (BCMA), a biological tag found on the surface of the cells mature plasmas. Note that although this antigen is a common target for myeloma treatments, it is under investigation to identify more potential targets.
Shortcomings of CAR T therapy
The process of extracting, genetically modifying, proliferating and infusing cells for each patient is a resource-intensive and expensive process, with a delay of a month or more. Most patients also require bridging therapy – treatments to control their disease while they wait. For this reason, only a minority of patients proceed with CAR T.
One possible solution is to have pre-prepared CAR T cells that many patients could use instead of cells tailored to a single individual. Many have described it as “available”. The researchers believe that a ready-made CAR T product could be administered in a few days and reduce the costs associated with manufacturing and bridging therapy. Here, we describe the results of clinical trials using ready-made CAR T cells to treat patients with multiple myeloma.
Commercialized CAR T cells
To make CAR T cells available, Mailankody et al. took T cells from three healthy donors and engineered them with novel chimeric antigen receptors (CARs) in place of a patient’s cells. The risk with this method is that the body may reject the donor’s cells, as is often the case with tissue transplants. Accordingly, the researchers’ CAR T study design and protocol address major hurdles such as graft-versus-host disease (GvHD) and rejection of CAR T cells.
The researchers used three safety features to reduce tissue rejection. First, they modified a familiar design of CAR T cells used for myeloma. Typical components include an anti-BCMA antibody fragment to detect plasma cells; a costimulatory molecule 4-1BB to support cell survival and proliferation; and a CD3γ signaling domain to release cancer-killing chemicals. The notable new addition is the off switch illustrated in Figure 1. This off switch allows the team to turn off the CAR T cells if needed by implementing a monoclonal antibody called rituximab .
Next, the team stopped the expression of a gene called T cell receptor alpha constant (TRAC) in the CAR T cells. They used gene-editing enzymes called transcription activator-like effector nucleases (TALENs for short) that can recognize and remove this gene associated with graft-versus-host disease. The knockout reduces the expression of T cell receptor complexes (Figure 2) on the surface of CAR T cells. With fewer receptors to communicate with, host T cells are less likely to recognize CAR T cells and eliminate them.
Finally, the researchers modified the usual preparation procedures. Patients are usually started on an immunosuppressive therapy called lymphodepletion before the CAR T-cell infusion. In addition to this standard practice, the team incorporated a new monoclonal antibody to eliminate threats before they become enemies. The monoclonal antibody targets host immune cells with CD52 glycoprotein on their surface. These host cells can mediate graft-versus-host disease and would counteract CAR T infusion if left alone. With this imminent threat removed, CAR T cells are free to proliferate.
Promote safety and tolerability outcomes
A total of 43 patients received a lymphodepletion regimen and escalating doses of the experimental CAR T-cell infusion (see Figure 3). These patients failed at least three prior lines of treatment, none with prior exposure to BCMA-directed CAR T therapy. Lymphodepletion was given up to five days before infusion. Patients did not require treatment to manage their cancer between enrollment and infusion of CAR T cells.
Adverse events
The trial produced promising safety profile results. None of the patients experienced graft-versus-host disease. The authors attribute this success to the knockout of the T-cell receptor (TRAC) gene. This does not mean, however, that there are no negative responses to therapy. All 43 patients experienced an adverse event, but none were sufficient to terminate the trial.
The most common CAR T side effects are cytokine release syndrome and neurotoxicity. Both conditions are caused by the profuse release of immune chemicals, and the severity of side effects increases on a scale of one to four, with one representing mild symptoms to four life-threatening. Half of the patients experienced mild to moderate cytokine release syndrome and 14% percent experienced mild to moderate neurotoxicity. Only one person experienced grade 3 or higher neurotoxicity, which is a slightly smaller but notable difference from the rates of other anti-myeloma CAR T therapies.
The use of a novel monoclonal antibody during the lymphodepletion regimen did not appear to increase the number of serious infections compared with other tailored myeloma CAR T therapies. However, the authors recommend viral monitoring for cytomegalovirus (CMV), a common virus that many carry but does not affect healthy people. The monoclonal antibody increases the risk of reactivation of this virus, and the infection should be treated with prophylaxis.
Response rates
CAR T therapy was well tolerated. The trial yielded an overall response rate of 56%. The group that received a dose of 320 million CAR T cells had a promising response rate of 71% with a median duration of response of 8.3 months. As shown in Figure 4, six people in this cohort had undetectable signs of their multiple myeloma.
looking ahead
A ready, universal CAR T therapy may not be a distant dream. Early results from the UNIVERSAL trial demonstrate that available CAR T cells can work safely if the cell design and lymphodepletion regimen accurately address potential donor rejection. These cells represent a possible solution to reduce labor, manufacturing and time costs associated with already established CAR T therapy for multiple myeloma.
Despite this, available CAR T therapy can still be prohibitively expensive for most people who need it. This underlying problem of access may require other improved technologies such as the use of mRNA to modify cells live, too.
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