Gene therapy for SCID-X1 may successfully reset immune system

NEW ORLEANS – Tweaking experimental gene therapy for X-linked severe combined immunodeficiency may help to restore patient immune function while reducing the risk for subsequent leukemias.

In a small, multinational phase I/II trial, seven of nine children with SCID-X1 showed evidence of T-cell recovery and function, as well as a lower risk for promoting growth of leukemic cells, when a self-inactivating gamma-retroviral vector (SCID-2) was used to promote reconstitution of the child’s immune system without insertional oncogenesis, reported Dr. Sung-Yun Pai at the annual meeting of the American Society of Hematology.

"Outcomes for boys who do not have well-matched donors are suboptimal, and it’s particularly for these boys that we are targeting gene therapy," said Dr. Pai, of Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston.

In previous gene therapy trials, investigators used the Moloney leukemia virus (MLV)-based gamma-retroviral vector (SCID-1) with strong promoters and enhancers to express an IL-2 receptor that reconstituted the immune system successfully in 18 of 20 boys.

However, 5 of the 20 boys developed T-cell acute lymphoblastic leukemia; 1 of the children died, and the remaining 4 were successfully treated.

The investigators found that in the patients with leukemia, the SCID-1 vector had inserted into a chromosomal region close to proto-oncogenes such as LMO2, and the enhancers were driving expression of the neighboring oncogene, promoting expression of aberrant T cells. The vector was subsequently modified with the goal of improved safety but similar efficacy to the original, said Dr. Pai. The strong viral enhancers were removed to prevent accident enhancement should the inserted genes manage to find their way into oncogenes.

The phase I/II study is being conducted in London, Paris, Boston, Cincinnati, and Los Angeles, and to date has enrolled 9 male children of a planned 20.

Of the 9, one child died from a preexisting adenoviral infection before immune recovery was complete, and one child did not have engraftment of the gene-marked cells and went on to transplant.

"The other patients have 9 months to 36 months of follow-up, they have evidence of T-cell recovery, of T-cell function, have cleared SCID-related infections, and are all out of hospital, healthy at home, [and] leading essentially normal lives."

When the investigators looked at the comparative efficacy of the SCID-1 and SCID-2 vectors, they saw that 6 months after gene therapy, there was no significant difference in the median number of T cells generated.

"It’s far too early to comment on whether this vector will truly be safer in terms of leukemia," Dr. Pai said, noting that in the SCID-1 trial the leukemias developed 3-5 years after gene therapy, and the longest follow-up in the SCID-2 study is only 3 years.

The investigators are, however, conducting molecular surrogate safety analyses looking at gene insertion sites from the blood of patients treated with SCID-1 and are comparing those sites with the vector-insertion sites in cells from patients in SCID-2.

Looking at a global genomewide map of integrations, they found no significant differences between SCID-1 and SCID-2. However, when they focused on 38 genes that are to be proto-oncogenes in lymphoid cancer, they found that significantly more integration of the modified genes occurred in proximity to the oncogenes in SCID-1 than in SCID-2 (P = .003).

"We hope that these data suggest that the modified SCID vector will show less capacity to drive aberrant cell growth and lead to less leukemogenesis," said Dr. Pai.

SCID-X1 is caused by inherited mutations in the gamma subunit of the interleukin (IL)-2 receptor. As a result, males are born without T lymphocytes or natural killer cells. Without a bone marrow or stem cell transplantation, children with the disease die early from opportunistic or community-acquired infections.

"These are really paradigm-changing results for mortally wounded children," said Dr. Laurence James Neil Cooper of the University of Texas M.D. Anderson Cancer Center in Houston, who moderated the briefing but was not involved in the study.

The trial is being sponsored by Children’s Hospital Boston, Cincinnati Children’s Hospital Medical Center, and the University of California, Los Angeles. Dr. Pai and Dr. Cooper reported having no relevant conflicts of interest.

NEW ORLEANS – Tweaking experimental gene therapy for X-linked severe combined immunodeficiency may help to restore patient immune function while reducing the risk for subsequent leukemias.

In a small, multinational phase I/II trial, seven of nine children with SCID-X1 showed evidence of T-cell recovery and function, as well as a lower risk for promoting growth of leukemic cells, when a self-inactivating gamma-retroviral vector (SCID-2) was used to promote reconstitution of the child’s immune system without insertional oncogenesis, reported Dr. Sung-Yun Pai at the annual meeting of the American Society of Hematology.

"Outcomes for boys who do not have well-matched donors are suboptimal, and it’s particularly for these boys that we are targeting gene therapy," said Dr. Pai, of Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston.

In previous gene therapy trials, investigators used the Moloney leukemia virus (MLV)-based gamma-retroviral vector (SCID-1) with strong promoters and enhancers to express an IL-2 receptor that reconstituted the immune system successfully in 18 of 20 boys.

However, 5 of the 20 boys developed T-cell acute lymphoblastic leukemia; 1 of the children died, and the remaining 4 were successfully treated.

The investigators found that in the patients with leukemia, the SCID-1 vector had inserted into a chromosomal region close to proto-oncogenes such as LMO2, and the enhancers were driving expression of the neighboring oncogene, promoting expression of aberrant T cells. The vector was subsequently modified with the goal of improved safety but similar efficacy to the original, said Dr. Pai. The strong viral enhancers were removed to prevent accident enhancement should the inserted genes manage to find their way into oncogenes.

The phase I/II study is being conducted in London, Paris, Boston, Cincinnati, and Los Angeles, and to date has enrolled 9 male children of a planned 20.

Of the 9, one child died from a preexisting adenoviral infection before immune recovery was complete, and one child did not have engraftment of the gene-marked cells and went on to transplant.

"The other patients have 9 months to 36 months of follow-up, they have evidence of T-cell recovery, of T-cell function, have cleared SCID-related infections, and are all out of hospital, healthy at home, [and] leading essentially normal lives."

When the investigators looked at the comparative efficacy of the SCID-1 and SCID-2 vectors, they saw that 6 months after gene therapy, there was no significant difference in the median number of T cells generated.

"It’s far too early to comment on whether this vector will truly be safer in terms of leukemia," Dr. Pai said, noting that in the SCID-1 trial the leukemias developed 3-5 years after gene therapy, and the longest follow-up in the SCID-2 study is only 3 years.

The investigators are, however, conducting molecular surrogate safety analyses looking at gene insertion sites from the blood of patients treated with SCID-1 and are comparing those sites with the vector-insertion sites in cells from patients in SCID-2.

Looking at a global genomewide map of integrations, they found no significant differences between SCID-1 and SCID-2. However, when they focused on 38 genes that are to be proto-oncogenes in lymphoid cancer, they found that significantly more integration of the modified genes occurred in proximity to the oncogenes in SCID-1 than in SCID-2 (P = .003).

"We hope that these data suggest that the modified SCID vector will show less capacity to drive aberrant cell growth and lead to less leukemogenesis," said Dr. Pai.

SCID-X1 is caused by inherited mutations in the gamma subunit of the interleukin (IL)-2 receptor. As a result, males are born without T lymphocytes or natural killer cells. Without a bone marrow or stem cell transplantation, children with the disease die early from opportunistic or community-acquired infections.

"These are really paradigm-changing results for mortally wounded children," said Dr. Laurence James Neil Cooper of the University of Texas M.D. Anderson Cancer Center in Houston, who moderated the briefing but was not involved in the study.

The trial is being sponsored by Children’s Hospital Boston, Cincinnati Children’s Hospital Medical Center, and the University of California, Los Angeles. Dr. Pai and Dr. Cooper reported having no relevant conflicts of interest.

NEW ORLEANS – Tweaking experimental gene therapy for X-linked severe combined immunodeficiency may help to restore patient immune function while reducing the risk for subsequent leukemias.

In a small, multinational phase I/II trial, seven of nine children with SCID-X1 showed evidence of T-cell recovery and function, as well as a lower risk for promoting growth of leukemic cells, when a self-inactivating gamma-retroviral vector (SCID-2) was used to promote reconstitution of the child’s immune system without insertional oncogenesis, reported Dr. Sung-Yun Pai at the annual meeting of the American Society of Hematology.

"Outcomes for boys who do not have well-matched donors are suboptimal, and it’s particularly for these boys that we are targeting gene therapy," said Dr. Pai, of Boston Children’s Hospital and the Dana-Farber Cancer Institute, Boston.

In previous gene therapy trials, investigators used the Moloney leukemia virus (MLV)-based gamma-retroviral vector (SCID-1) with strong promoters and enhancers to express an IL-2 receptor that reconstituted the immune system successfully in 18 of 20 boys.

However, 5 of the 20 boys developed T-cell acute lymphoblastic leukemia; 1 of the children died, and the remaining 4 were successfully treated.

The investigators found that in the patients with leukemia, the SCID-1 vector had inserted into a chromosomal region close to proto-oncogenes such as LMO2, and the enhancers were driving expression of the neighboring oncogene, promoting expression of aberrant T cells. The vector was subsequently modified with the goal of improved safety but similar efficacy to the original, said Dr. Pai. The strong viral enhancers were removed to prevent accident enhancement should the inserted genes manage to find their way into oncogenes.

The phase I/II study is being conducted in London, Paris, Boston, Cincinnati, and Los Angeles, and to date has enrolled 9 male children of a planned 20.

Of the 9, one child died from a preexisting adenoviral infection before immune recovery was complete, and one child did not have engraftment of the gene-marked cells and went on to transplant.

"The other patients have 9 months to 36 months of follow-up, they have evidence of T-cell recovery, of T-cell function, have cleared SCID-related infections, and are all out of hospital, healthy at home, [and] leading essentially normal lives."

When the investigators looked at the comparative efficacy of the SCID-1 and SCID-2 vectors, they saw that 6 months after gene therapy, there was no significant difference in the median number of T cells generated.

"It’s far too early to comment on whether this vector will truly be safer in terms of leukemia," Dr. Pai said, noting that in the SCID-1 trial the leukemias developed 3-5 years after gene therapy, and the longest follow-up in the SCID-2 study is only 3 years.

The investigators are, however, conducting molecular surrogate safety analyses looking at gene insertion sites from the blood of patients treated with SCID-1 and are comparing those sites with the vector-insertion sites in cells from patients in SCID-2.

Looking at a global genomewide map of integrations, they found no significant differences between SCID-1 and SCID-2. However, when they focused on 38 genes that are to be proto-oncogenes in lymphoid cancer, they found that significantly more integration of the modified genes occurred in proximity to the oncogenes in SCID-1 than in SCID-2 (P = .003).

"We hope that these data suggest that the modified SCID vector will show less capacity to drive aberrant cell growth and lead to less leukemogenesis," said Dr. Pai.

SCID-X1 is caused by inherited mutations in the gamma subunit of the interleukin (IL)-2 receptor. As a result, males are born without T lymphocytes or natural killer cells. Without a bone marrow or stem cell transplantation, children with the disease die early from opportunistic or community-acquired infections.

"These are really paradigm-changing results for mortally wounded children," said Dr. Laurence James Neil Cooper of the University of Texas M.D. Anderson Cancer Center in Houston, who moderated the briefing but was not involved in the study.

The trial is being sponsored by Children’s Hospital Boston, Cincinnati Children’s Hospital Medical Center, and the University of California, Los Angeles. Dr. Pai and Dr. Cooper reported having no relevant conflicts of interest.