Trivalent CAR T-Cell Design May Enhance Antitumor Efficacy in Acute Lymphoblastic Leukemia


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A novel approach to chimeric antigen receptor (CAR) T-cell therapy seems to effectively target acute lymphoblastic leukemia (ALL) cells with varying antigen profiles and may help to overcome antigen escape, seen with CD19-targeted therapy. According to data presented at the 2018 ASCO-SITC Clinical Immuno-Oncology Symposium, by targeting CD19, CD20, and CD22 antigens with trivalent CAR T cells, researchers have managed to mitigate CD19-negative relapse in a laboratory study, resulting in enhanced antitumor efficacy.1 This strategy has the potential for use as an initial CAR T-cell therapy in relapsed ALL or a salvage therapy for patients with CD19-negative disease, the authors noted.

“Overall, trivalent CAR T cells have been found to be efficacious against primary ALL of varying antigen profiles,” said Kristen Fousek, MS, a predoctoral fellow at Baylor College of Medicine. “These data also show trivalent CAR T cells to be better “serial killers” than CD19 CAR T cells due, in part, to increased cell activation. Most important, trivalent CAR T cells kill CD19-negative primary ALL.”

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As Ms. Fousek reported, although CD19 CAR T-cell therapy has changed the paradigm in relapsed or refractory ALL, longer follow-up has shown that up to 40% of patients who relapse after CAR T-cell therapy have CD19-negative disease. Moreover, in a recent CD22-targeted CAR T-cell trial, investigators found that in a subset of patients who experiences relapse, seven of eight did so with decreased expression of CD22 on the leukemia cell surface.2 

“This is not a phenomenon specific to CD19, but rather something specific to targeting only a single antigen,” explained Ms. Fousek.

To combat CD19 antigen escape, Ms. Fousek and colleagues first conducted an analysis of three samples of ALL. Although all three ubiquitously expressed CD19, two other antigens, CD20 and CD22, had more heterogeneous expression. CD22 was expressed in most B-cell ALL, said Ms. Fousek, and there were high levels of CD20 expression on more mature ALL or lymphomas. 

Using a single DNA vector that had each CAR-encoding segment included, separated by self-cleaving viral 2A peptides, the investigators then designed a CAR T-cell product in which a single T cell expressed three individual CARs on its surface.

Increased Efficacy Against Primary ALL

In a short-term killing assay, trivalent CAR T cells were found to be efficacious in killing target cells of all three primary ALLs of varying antigen profile. In fact, said Ms. Fousek, researchers observed a “substantial increase in efficacy” over CD19 CAR T cells, as measured by the time to find the target cell, the length of time between conjugation and detachment, and the time to cell death.

“This experiment showed that trivalent CAR T cells are more efficient than CD19 CAR T cells at killing target cells, as well as subsequent targets, with a shorter time to cell death,” said Ms. Fousek. “This increase in effectiveness and efficiency of killing was also extrapolated to larger frequency of killing, so these cells prove to better “serial killers” than their CD19 counterparts.”

In addition, Ms. Fousek and colleagues examined the effectiveness of trivalent CAR T-cell therapy in the absence of CD19 to model CD19-negative disease. Using CRISPR (clustered regularly interspaced short palindromic repeats) technology, the researchers “knocked out” CD19 in a primary ALL cell line, which also decreased some expression of CD20 and CD22. Despite the absence of CD19, however, trivalent CAR T cells still mitigated CD19-negative relapse, producing interferon-gamma and tumor necrosis factor alpha, and killing CD19-negative primary ALL. CD19 CAR T cells, on the other hand, remained ineffective, unable to produce key cytokines when CD19 was not present.

Finally, the researchers wanted to know whether trivalent CAR T cells can kill CD19 escape variants. Although CD19 CAR T cells are able to lyse primary TXL-2 cells, said Ms. Fousek, only trivalent CAR T cells are able to kill primary CD19-negative variants of ALL.

While ongoing studies in mice and other primary ALL models are testing the efficacy of trivalent T-cell therapy in vivo, Ms. Fousek and colleagues are considering additional antigen targets as well as combining other therapeutic modalities. Furthermore, the researchers hope to establish whether trivalent CAR T cells are better suited for a salvage therapy after a CD19 loss or initial upfront CAR T-cell therapy against primary ALL. ■

DISCLOSURE: Ms. Fousek reported no conflicts of interest.

REFERENCES

1. Fousek K, Watanabe J, George A, et al: Targeting CD19-negative relapsed B-acute lymphoblastic leukemia using trivalent CAR T cells. 2018 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 121. Presented January 26, 2018.

2. Maxson JE, Gotlib J, Pollyea DA, et al: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML. N Engl J Med 368:1781-1790, 2013.


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