NEW YORK & MEMPHIS, Tenn.—X-linked severe combined immunodeficiency (X-SCID), or “bubble boy” disease, affects about one or two in 100,000 live births worldwide. The rare and often fatal inherited disease is caused by a lack of immune cells needed to ward off viruses, bacteria and fungi. While bone marrow transplantation has been the most effective treatment, more than 80 percent of children with X-SCID cannot get fully matched cell donors, and the one-third who receive transplants develop immune problems continuing for many years. Now, however, there may be a solution.

St. Jude Children’s Research Hospital has created the lentiviral vector to deliver a healthy copy of the IL2RG gene into a child’s blood-forming cells. Thus far, the therapy has demonstrated results that have enabled children to return to their normal lives, according to clinical trial results.

Mustang Bio, a Fortress Biotech company, has entered a partnership and exclusive license deal with St. Jude to develop a first-in-class ex-vivo lentiviral gene therapy for children with X-SCID. The therapy is under evaluation by St. Jude and others in a Phase 1/2 trial in infants under two, and by the National Institutes of Health (NIH) in a Phase 1/2 trial in patients over the age of two—the world’s first lentiviral gene therapy trial for infants with X-SCID.

According to Mustang’s CEO Manny Lichtman, patients with X-SCID do not survive beyond infancy without treatment. The standard of care is allogeneic hematopoietic stem cell transplantation (HSCT). While results are good following HSCT from a matched sibling donor, 90 percent of patients only have the option of a haploidentical donor, and their overall survival rate is only 60 to 75 percent.

Lichtman continued, “In addition, many of the patients transplanted from haploidentical donors continue to experience infections due to significant impairment of immunity, with 28 percent experiencing acute graft-versus-host disease (GvHD) and 15 percent suffering with chronic GvHD. Moreover, 26 percent of patients transplanted from haploidentical donors require a second HSCT due to poor T-cell reconstitution.”

Mustang has built a team of viral vector, manufacturing and cell processing experts at its Worcester, Mass., cell processing and research facility to support its portfolio of six chimeric antigen receptor T cell (CAR-T) therapies.

St. Jude’s approach to the X-SCID gene therapy program is analogous to the CAR-T approach, with two major differences: (1) the transduced cells are hematopoietic stem cells and (2) there is no need for prolonged incubation of the cells. Therefore, as a result of the team’s breadth of experience in CAR-T, the players are in a position to advance this new gene therapy collaboration.

Mustang began in 2015 via a licensing agreement with City of Hope National Medical Center (COH) for two preclinical CAR T programs: an IL13Rα2-specific CAR-T therapy for the treatment of glioblastoma and CD123 CAR-T therapy. These programs have since entered Phase 1 clinical trials at COH.

The COH collaboration was expanded in June 2017 with the addition of three preclinical CAR-T programs: human epidermal growth factor receptor 2 (HER2) CAR-T technology, which will initially be applied in the treatment of glioblastoma multiforme; CS1-specific CAR-T technology to be directed against multiple myeloma; and prostate stem cell antigen (PSCA) CAR-T technology to be used in the treatment of prostate and pancreatic cancer. All of these programs are expected to enter Phase 1 trials within the next 12 months.

Mustang added a sixth preclinical CAR-T program to its portfolio in September 2017 via a licensing agreement with Fred Hutchinson Cancer Research Center. The CD20-directed CAR-T is in a Phase 1/2 investigator-initiated trial in B cell non-Hodgkin lymphoma.

Mustang’s parent company, Fortress Biotech, learned of the clinical results achieved by both St. Jude and the NIH in the X-SCID gene therapy program and negotiated a license to the technology. “Due to Mustang’s cell therapy manufacturing capabilities, the X-SCID program fits naturally into our portfolio,” Lichtman said.

Data from two clinical trials have been disclosed: a Phase 1/2 multicenter trial in infants under the age of two led by St. Jude, and a Phase 1/2 single-center trial in patients over the age of two at the NIH. In the St. Jude trial, eight infants not yet treated with HSCT underwent X-SCID gene therapy following treatment with a low dose of the chemotherapeutic agent busulfan. According to Lichtman, “As reported at the 21st Annual Meeting of the American Society of Gene & Cell Therapy in May 2018, the gene therapy was well tolerated. Six patients achieved reconstituted immune systems within three to four months following treatment, with the remaining two patients continuing to progress favorably in earlier stages of recovery. Two of these six patients have discontinued monthly infusions of intravenous immunoglobulin, and the remaining patients, at earlier stages of recovery, continue to progress favorably. In three patients who had disseminated infections prior to therapy, all infections resolved completely.”

He added, “In the NIH trial, five patients aged 10 to 23 years with progressively declining persistent immune dysfunction after haploidentical HSCT in infancy underwent X-SCID gene therapy following treatment with low-dose busulfan. The gene therapy appears to be safe, and follow-up data from two older patients demonstrated immune system reconstitution and clinical improvement at two to three years following treatment. In three younger patients, similar levels of gene-modified immune cells were also observed at six to nine months following treatment.”

Lichtman concluded, “We expect between 39 and 77 new cases in the U.S., between 51 and 102 new cases in Europe and between nine and 19 new cases in Japan each year. Currently, there may be as many as 1,000 to 1,500 X-SCID patients in the U.S., and a similar number in Europe, who continue to have significant impairment of immunity despite receiving previous allogeneic HSCT and who therefore could be eligible for this gene therapy.”