In a chemotherapeutic lymphocyte depleting regimen for one week.

In 2018 with an estimated 1,735,350 new cancer cases predicted to be diagnosed in the United States, with 609,640 predicted to be fatal, cancer is at the forefront of global research efforts 1. One of the most devastating forms of cancer is Leukemia, which is cancer of the blood-forming tissues of the body. Originating as B-cells, these so called B-lineage cells become mutated to the point where they are no longer functional. While chemotherapeutic treatments are available, they are not always successful and more often than not result in crippling side effects.

In an attempt to develop an alternative to traditional chemotherapeutics, researchers at the National Cancer Institute in Bethesda, Maryland 2 have developed a novel method for harvesting and reprograming the patient’s own immune cells to combat the lymphoma. The researcher’s hypothesize that by creating a chimeric antigen receptor (CARs) on the surface of T-cells could result in an eradication of B-lineage cells, ultimately resulting in a regression of lymphoma. The CAR they designed contains variable regions of monoclonal antibodies, for CD19 recognition, joined with CD28 and signaling domains from CD3?, which facilitate proper signal transduction.

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After designing and testing the hypothetical CAR molecule, the researchers applied for and were granted permission to conduct an in-human clinical trial. The patient’s peripheral blood mononuclear cells (including T cells, B cells, and NK cells) were removed and T cell specific proliferation was induced. Retroviruses encoding for the anti-CD19 CAR were then used to transduce the cells. Once the cells were in possession of the CAR gene, proliferation was again induced to create sufficient cells for infusion into the patient. Through flow cytometry, the researchers were able to confirm that 64% of the final cell count was expressing CAR, and of those, 98% were CD3+ T cells.

To prepare the patient for CAR-T infusion, the patient received a chemotherapeutic lymphocyte depleting regimen for one week. The day following the last dose of chemotherapeutic, 100 million anti-CD19-CAR T cells were delivered intravenously. The following day 300 million additional cells were delivered. IL-2 infusions were performed for two days after the final cell infusion to limit the experienced toxicity. The patient was released eleven days after the final cell infusion, and was able to resume full-time employment.

After the therapy, the patient experienced partial remission of the lymphoma that lasted 32 weeks. Furthermore, Blood B cells were found to be absent from weeks 9-39 after cell infusion, suggesting that the therapy was highly effective at depleting B-linage cells. It was also found that all patient blood cell counts had returned to normal within nine weeks of the treatment, suggesting a high level of specificity in the therapy. Serum IgG levels were found to be below detectable range from 9-39 weeks after treatment, and resulted in a minor infection in the patient. The patient now received intravenous Ig replacement, and has no problem with recurrent infections.

Overall, the trial concluded that the CAR-T therapy was a viable method for not only reduction of B-lineage cells, but also induction of lymphoma remission. This conclusion is consistent with the inability to detect blood B-cells as well as the patient’s 32 week remission. As CAR-T therapies continue to be developed, more and more research institutions are becoming involved. This CAR based therapy is showing exceptional promise for the treatment of cancers of various types, and will likely be heavily utilized in the future.

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