GENE-MODIFIED HEMATOPOIETIC STEM/PROGENITOR CELL BASED THERAPY FOR HIV DISEASE

GENE-MODIFIED HEMATOPOIETIC STEM/PROGENITOR CELL BASED THERAPY FOR HIV DISEASE

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-06893
Investigator: 
Award Value: 
$8,278,722
Disease Focus: 
HIV/AIDS
Stem Cell Use: 
Adult Stem Cell
Status: 
Active
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 

Year 1

CAL-USA-11 is a Phase I/II human study designed to assess the safety, feasibility, and tolerability of the Cal-1 product in HIV-infected individuals who have previously been on ART but are not currently taking any antiretroviral agent. The objective of the Cal-1 therapy is to increase the number of protected cells in the body of an individual infected with HIV to the point where the virus is incapable of causing harm. This would potentially reduce or eliminate the need for a lifetime of antiretroviral therapy. In 1996, scientists determined that CCR5 is the primary co-receptor by which HIV enters and infects T cells. Most people inherit two normal copies (one from each parent) of the gene that codes for the CCR5 protein. However, about 1% of the European population has a mutation in both of these copies. Because they do not produce any CCR5, these individuals are naturally resistant to HIV infection. This clinical trial is a first-in-human test of Calimmune’s one-time outpatient gene therapy that has been designed to confer a similar genetic resistance to the T cells and hematopoietic stem/progenitor cells of HIV-infected patients. This will be accomplished by reducing CCR5 expression through a process called RNA interference (RNAi), and preventing HIV entry through the use of a membrane-bound fusion inhibitor. As such, our approach seeks to protect target cells from HIV via two distinct mechanisms. The potential benefit of this combined approach is twofold: Because we are treating stem cells along with T cells, we will be creating the potential for the progeny of the stem cells to also exhibit genetic resistance to HIV and therefore repopulate the participant’s immune system; and because we are utilizing a dual therapy, we minimize the possibility of cellular infection via different or mutated HIV strains. The study is enrolling participants at sites in Los Angeles and San Francisco, Calif., under the direction of Principal Investigators Ronald Mitsuyasu, M.D., of UCLA and Jacob P. Lalezari, M.D., of Quest Clinical Research in San Francisco. The first participant was infused with Cal-1 treated T cells and hematopoietic stem/progenitor cells (HSPC) in June 2013. Since then, additional participants have also been infused. The study has three arms. All participants will receive the Cal-1 product. Participants in two of the three study arms will also receive different doses of a drug known as busulfan prior to the infusion, which has the potential to make the therapy more effective. Laboratory assessments performed throughout the course of the study will monitor: • the participants’ general health and level of HIV infection; • the participants’ level of CD4+ T cells; • the presence of Cal-1 modified cells in various cell types in the blood and lymphoid tissue; and • the safety of the approach. The primary objectives of the study are to evaluate: • The safety, feasibility, and tolerability of Cal-1 gene-transduced hematopoietic cell populations. • The safety and tolerability of low- and moderate-dose busulfan as a non-myeloablative conditioning agent as a means to improve engraftment of transduced HSPC. The study is open to men and women ages 18 to 65 who are HIV-infected but do not have any other serious medical conditions. Participants must have been well-controlled on ART in the past, but must not be taking ART currently. Full details of the study are available at: http://www.clinicaltrials.gov/ct2/show/NCT01734850?term=NCT01734850&rank=1

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