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By Vien Lai

For many reasons, no gene-cell therapies have been approved by the Food and Drug Administration (FDA). However, one recent modified-cell biological product is changing that status. This product potentially cures a rare and difficult to treat relapsed/refractory B-cell acute lymphoblastic leukemia (acute lymphocytic leukemia [ALL]). As with many complicated drug products, FDA asked the Oncologic Drugs Advisory Committee (ODAC) for advice with evaluation and approval.

In a meeting on July 12, 2017, the ODAC evaluated the initial clinical results and voted 10/0 in favor of the product, Tisagenlecleuce (manufactured by Novartis; BLA 125646), which contains reprogrammed autologous T cells overexpressing a chimeric antigen receptor (CAR) targeting B-cell ALL. The ODAC also recommended FDA approve Tisagenlecleuce for the treatment of relapsed/refractory B-cell ALL in patients 3 to 25 years of age. If approved as recommended, Tisagenlecleuce will be the first-in-class biological gene-cell product.

Gene-Cell Biologic Background

Gene-cell biologic products are novel and complex in regard to the scientific and regulatory processes involved.

Leukocytes, part of the white blood cells, are the central part of the immune system responsible for fighting against infection and eliminating foreign bodies including cancer cells. There are three main types of lymphocytes: T cells, B cells, and natural killer cells.

ALL is a cancer of the lymphocytes. In ALL, the cancerous lymphoblasts are produced uncontrollably in the bone marrow. Over-production of the immature, nonfunctional lymphoblasts inhibits production of other cell lines (such as red blood cells and platelets). These cancer lymphoblasts circulate throughout the blood stream, invade, and cause damage to other organs. In general, depending on the expression of cell surface markers, ALL can be classified as B-cell ALL, T-cell ALL, and Burkitt ALL. Because these cancer cells develop from a mutated progenitor of the human body, the immune system does not recognize them as foreign bodies. Thus, the leukocytes do not do their job in eliminating the overproduced lymphoblasts.

Ex vivo reprogramming of human cells allows them to carry additional characteristics, which has been investigated for years. The modified cells, when transplanted back into the body with new characteristics, are expected to serve as primary sources for the targeted effects. These reprogrammed cells consist of, but are not limited to, modified progenitors for regenerative medicine, or engineered lymphocytes to target cancer cells.

Potential Drawbacks

Benefits are not without risks. One drawback of the treatment is that the protocol requires several weeks of processing time. Because these complex specific gene-cell biological products are highly customized, patients need to pre-order and wait for their products. In addition, as an autologous biologic, a patient will not benefit from a product that is intended for a different patient, unless he/she has a monozygotic twin.

As part of gene therapy using viral transduction, risks of carrying additional genes beside the targeted gene need further understanding and research. Nevertheless, in the study submitted to FDA, among the patients who were treated with Tisagenlecleuce, short-term follow up has not identified vector-related adverse events. Long-term studies will be required to confirm the safety of the gene-cell therapy approach. Certainly more patients need to be treated and monitored long term to truly assess the impact of this therapy and clinical performance.

Regulatory Perspectives

Notably, on January 31, 2014, a T lymphocytesCAR+ targeted CD19 product by Novartis obtained an orphan drug designation for treatment of ALL. Per the Orphan Drug Act, upon approval, Tisagenlecleuce will also be awarded an exclusive marketing period of seven years. It is unclear at this stage whether the exclusivity will prevent competition from other engineered autologous lymphocytes products carrying different CARs but also targeting CD19.

Who Else Will Benefit from Gene-Cell Therapy?

Gene-cell therapy is not only for cancer patients. Other diseases such as ischemic heart diseases and neural diseases may also benefit from gene-cell biologic therapies. Unlike in cancer therapy, the engineered cells in ischemic heart diseases or neural diseases will need to be programmed to resist a hostile environment, to differentiate to be functional cells, and to regenerate the lost tissue. However, it may take many more years until we can see a gene-cell biological product for regenerative being ready for approval.

Vien Lai, Ph.D., is a research scientist at Camargo Pharmaceutical Services, Cincinnati, Ohio.