Autologous Gene Therapy for Artemis-Deficient SCID

Официальное название

Phase I/II Safety and Efficacy Study of Gene Transfer for Artemis-Deficient Severe Combined Immunodeficiency (ART-SCID) in Newly Diagnosed Patients Using Self-Inactivating Lentiviral Vector (AProArt) to Transduce Autologous CD34 Hematopoietic Cells

Обзор

This study aims to determine if a new method can be used to treat Artemis-deficient Severe Combined Immunodeficiency (ART-SCID), a severe form of primary immunodeficiency caused by mutations in the DCLRE1C gene. This method involves transferring a normal copy of the DCLRE1C gene into stem cells of an affected patient. Participants will receive an infusion of stem cells transduced with a self-inactivating lentiviral vector that contains a normal copy of the DCLRE1C gene. Prior to the infusion they will receive sub-ablative, dose-targeted busulfan conditioning. The study will investigate if the procedure is safe, whether it can be done according to the methods described in the protocol, and whether the procedure will provide a normal immune system for the patient. A total of 24 newly diagnosed patients will be enrolled at the University of California San Francisco in this single-site trial and will be followed for 15 years post-infusion. It is hoped that this type of gene transfer may offer improved outcomes for ART-SCID patients who lack a brother or sister who can be used as a donor for stem cell transplantation or who have failed to develop a functioning immune system after a previous stem cell transplant.

Подробное описание

Children with SCID generally do not survive beyond the first year of life without definitive treatment. The most effective current cure is hematopoietic stem cell transplant (HCT) with a human leukocyte antigen (HLA) matched sibling. While a matched sibling HCT can successfully treat ART-SCID, fewer than 20% of affected children have such a donor, and even when a matched sibling donor is available there is often incomplete T and B cell immune reconstitution. ART-SCID is the most difficult type of SCID to cure by hematopoietic stem cell transplant using alternative donors. Engraftment typically requires intensive conditioning with high dose alkylating agents to prevent rejection and to open marrow niches. These patients also have a high risk of developing graft versus host disease (GVHD) when alternative donors are used. The great majority of patients have absent B cell reconstitution and require lifelong administration of immunoglobulin infusions. Patients with ART-SCID who do receive high doses of alkylators, especially when 2 agents are used, have poorer survival, abnormal dental development, endocrinopathies, and short stature in comparison with children exposed to no or limited alkylators or children with SCID types that are not associated with a DNA repair defect. For these reasons, a safer, more effective approach to curing ART-SCID is needed. Autologous gene-corrected hematopoeitic stem cell transplant may eliminate both the risk of GVHD and the need for alkylators to prevent rejection.

The study design is a single-cohort, longitudinal experiment using non-randomized patients treated once with a lentiviral vector for gene-correction of Artemis-deficient SCID after conditioning with low-dose busulfan. No formal control group is planned for gauging safety; rather, intensive monitoring of the initial 6 enrollees was undertaken to preclude continued accrual in the presence of safety signals. This enrollment stage was completed in 2019 with no safety signals identified, and long-term safety will be monitored for 15 years. Bone marrow stem cells will be harvested from participants, and CD34 cells will be isolated using the CliniMACS® CD34 Reagent System cell sorter device. The CD34 cells will be transduced with the AProArt lentiviral vector, and cryopreserved. Aliquots of the cells will undergo safety testing and be reserved for potency evaluation. All patients will receive busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg\*hr/L (an ablative cumulative AUC is 60-90mg\*hr/L).

Following the infusion of AProArt-transduced cells, patients will be assessed weekly through 12 weeks post-transplant and at week 16, monthly through month 6 post-transplant, every 3 months through month 24, every 6 months during years 2-5, and then annually through year 15. Assessments will include physical examination, clinical laboratory tests, collection of specimens for research studies, and completion of Quality of Life questionnaires. Neurodevelopmental testing will be performed at age-appropriate time points.

At weeks 4, 6, 8, 12, 16, and 24, research specimens will be evaluated for evidence of gene transduced peripheral blood mononuclear cells and when possible, cell lineages including T, B, NK and granulocyte/myeloid cells. If there is no evidence of gene transduced cells at 6 weeks (42 days) post infusion, planning for an alternative treatment will begin, with the final decision regarding further therapy to be based on gene-marking results at 10 weeks.

If the absolute neutrophil count is \< 200/µl or platelets \< 20,000/µl on 3 independent determinations after day 42 post infusion of transduced cells, the patient may receive an allogeneic hematopoeitic stem cell transplant. Patients who were neutropenic prior to conditioning (SCID-related neutropenia) but responsive to granulocyte-colony stimulating factor (GCSF) will not be considered to have failed, provided the absolute neutrophil count can be maintained above \>300/µl with GCSF.

Recipients will be followed for toxicity and durable reconstitution of T and B cell immunity. Immune reconstitution of T cells will be monitored on a regular basis. Patients with evidence of clinically inadequate immune reconstitution, low vector copy number (VCN), or any other features suggesting clinically inadequate response to the initial gene therapy procedure will be offered a repeat infusion of gene-transduced cells. Conditioning regimens given prior to a repeat gene therapy procedure may include low-dose busulfan, other conditioning, or no conditioning.

Historical controls who received alternative donor allogeneic transplants as treatment for ART-SCID will serve as the comparator arm for secondary endpoints.

An independent Data Safety Monitoring Board (DSMB) has been appointed for safety monitoring of this trial. The DSMB reviews all data for safety on a regular schedule, based on numbers of enrolled subjects and conducts special urgent review of any protocol related Serious Adverse Events (SAE). In the early stage of the trial, the DSMB reviewed results of each of the first 3 cases prior to proceeding with subsequent patients.

The investigational product (IND17711) for the ART-SCID gene transfer study is not available for expanded access use. As per 21 CFR Part 312.305(3), the study management team has determined that providing the investigational product for expanded access use at this time would interfere with the conduct and completion of the clinical trial and potential development of future expanded access use. The investigational product is available to eligible patients through participation in this clinical trial.

Вмешательства

• Препарат AProArt-CD34
  Participants will undergo infusion with autologous hematopoietic cells transduced with a lentiviral vector, AProArt, which contains the correct form of DCLRE1C complementary deoxyribonucleic acid DNA, after receiving sub-ablative, exposure-targeted busulfan conditioning.
• Устройство CliniMACS® CD34 Reagent System cell sorter device
  Processing of hematopoietic progenitor cells to select CD34 cells, using the CliniMACS® CD34 Reagent System, prior to infusion.
• Препарат Busulfan
  Busulfan is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Patients will receive low-dose busulfan conditioning targeted over 2 days to achieve a cumulative area under the curve (AUC) of 20 mg\*hr/L.

Первичные конечные точки

• To demonstrate that ART-SCID patients receiving AProArt-CD34 infusion have superior overall survival (OS) at 24 months post treatment with AProArt-CD34 versus the established outcome of 0% OS for patients who receive no treatment for ART-SCID [Срок оценки: 24 months]

Вторичные конечные точки (3)

• B cell immune reconstitution by 24±2 months compared with historical control cohort of allogeneic transplant recipients [Срок оценки: 24 months]
• Number of participants with T cell immune reconstitution compared with historical controls who received allogeneic transplants to treat ART-SCID. [Срок оценки: 24 months]
• Event Free Survival [Срок оценки: 24 months]

Критерии участия

Критерии включения

• ≥2.0 months of age at initiation of busulfan conditioning
• New diagnosis of typical or minimally leaky ART-SCID, as defined by the criteria below:
• Artemis deficiency with bi-allelic pathogenic or likely pathogenic mutations in DCLRE1C; AND
• CD3 count < 50 autologous cells/µL (typical ART-SCID) OR spontaneous maternal chimerism, OR CD3 count >50/µL and <300/uL and with restricted T cell receptor Vb diversity; AND
• CD45 cell response to mitogens (PHA) < 50% of the lower limit of normal range for the lab (leaky ART-SCID).
• No medically eligible HLA-identical sibling with a normal immune system who could serve as an allogeneic bone marrow donor (applies to newly diagnosed patients only).

Критерии исключения

• Presence of a medically eligible HLA-matched sibling
• Evidence of HIV infection by polymerase chain reaction or p24 antigen testing.
• Unable to tolerate general anesthesia and/or marrow harvest or insertion of central venous catheter.
• Any one of liver function tests AST, ALT, gamma-glutamyl transpeptidase (GGT) >5X the upper limit of normal for lab and/or total bilirubin >2.0 mg/dl (not due to Gilbert's) at the time of planned initiation of busulfan conditioning unless the elevated LFTs are considered to be due to medication, a viral infection for which there is no treatment other than reconstituting T cell immunity, or maternal GVHD.
• Presence of any severe medical conditions making a patient unsuitable for busulfan administration
• Presence of a recognized second gene mutation that results in an autosomal dominant or recessive disorder intrinsic to hematopoietic cells and that could be treated by an allogeneic HCT.
• Presence of a medical condition indicating that survival is predicted to be less than 4 months, such as the requirement for mechanical ventilation, severe failure of a major organ system, or evidence of a serious, progressive infection that is refractory to medical therapy.
• A social situation indicating that the family may not be able to comply with protocol procedures and recommended medical care and follow-up.
• Other conditions which in the opinion of the Principal Investigator and/or co-investigators, contra-indicate the infusion of transduced cells or study participation.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of California, San Francisco (UCSF) Children's Hospital — San Francisco

Публикации

• Buckley RH. The multiple causes of human SCID. J Clin Invest. 2004 Nov;114(10):1409-11. doi: 10.1172/JCI23571. PMID 15545990
• Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968 Dec 28;2(7583):1366-9. doi: 10.1016/s0140-6736(68)92673-1. No abstract available. PMID 4177932
• Chan A, Scalchunes C, Boyle M, Puck JM. Early vs. delayed diagnosis of severe combined immunodeficiency: a family perspective survey. Clin Immunol. 2011 Jan;138(1):3-8. doi: 10.1016/j.clim.2010.09.010. Epub 2010 Oct 28. PMID 21035402
• Chan K, Puck JM. Development of population-based newborn screening for severe combined immunodeficiency. J Allergy Clin Immunol. 2005 Feb;115(2):391-8. doi: 10.1016/j.jaci.2004.10.012. PMID 15696101
• Kwan A, Puck JM. History and current status of newborn screening for severe combined immunodeficiency. Semin Perinatol. 2015 Apr;39(3):194-205. doi: 10.1053/j.semperi.2015.03.004. Epub 2015 Apr 30. PMID 25937517
• Pai SY, Logan BR, Griffith LM, Buckley RH, Parrott RE, Dvorak CC, Kapoor N, Hanson IC, Filipovich AH, Jyonouchi S, Sullivan KE, Small TN, Burroughs L, Skoda-Smith S, Haight AE, Grizzle A, Pulsipher MA, Chan KW, Fuleihan RL, Haddad E, Loechelt B, Aquino VM, Gillio A, Davis J, Knutsen A, Smith AR, Moore TB, Schroeder ML, Goldman FD, Connelly JA, Porteus MH, Xiang Q, Shearer WT, Fleisher TA, Kohn DB, PMID 25075835
• Dorsey MJ, Dvorak CC, Cowan MJ, Puck JM. Treatment of infants identified as having severe combined immunodeficiency by means of newborn screening. J Allergy Clin Immunol. 2017 Mar;139(3):733-742. doi: 10.1016/j.jaci.2017.01.005. PMID 28270365
• Dvorak CC, Hassan A, Slatter MA, Honig M, Lankester AC, Buckley RH, Pulsipher MA, Davis JH, Gungor T, Gabriel M, Bleesing JH, Bunin N, Sedlacek P, Connelly JA, Crawford DF, Notarangelo LD, Pai SY, Hassid J, Veys P, Gennery AR, Cowan MJ. Comparison of outcomes of hematopoietic stem cell transplantation without chemotherapy conditioning by using matched sibling and unrelated donors for treatment of PMID 25109802

Идентификаторы

NCT: NCT03538899 · 17-22799 · CLIN2-10830 · CLIN2-17127

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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