HIV/AIDS

Coding Dimension ID: 
293
Coding Dimension path name: 
HIV/AIDS
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-06893
Investigator: 
Institution: 
Type: 
PI
ICOC Funds Committed: 
$8 278 722
Disease Focus: 
HIV/AIDS
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Statement of Benefit to California: 
Progress Report: 
  • 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
  • Public Statement of Scientific Progress
  • 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. In June 2014, based on review of the safety data from the study’s first arm, Calimmune announced that it was given approval by its Data Safety Monitoring Board to move into the second study arm using busulfan.
  • 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
Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01431
Investigator: 
Name: 
Type: 
PI
Institution: 
Type: 
Co-PI
ICOC Funds Committed: 
$9 905 604
Disease Focus: 
HIV/AIDS
Immune Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Closed
Public Abstract: 
RNA interference is a naturally occurring means to block the function of genes in our body. We propose that RNA interference can be used to block HIV-1 infection and its reproduction within the body. When RNA interference is introduced into a stem cell, its blocking activity will be present throughout the lifetime of the stem cell, theoretically the lifespan of a human being. Thus, in theory an effective stem cell RNA interference therapy will require only a single treatment as opposed to the current lifetime administration of anti-HIV-1 drugs often accompanied by serious side effects. In nature, some individuals carry a genetic mutation that renders them resistant to HIV-1 infection. This mutation prevents HIV-1 from attaching to the white blood cells. Our RNA interference approach will be to mimic this natural situation by blocking the activity of this “co-receptor” within infected individuals by creating a new blood system that carries the RNA interference therapy. This therapy will be developed as a combination with other gene therapeutic reagents to protect the new blood system from HIV infection.
Statement of Benefit to California: 
The need for novel approaches to the treatment of HIV infection has never been greater, because new infections continue to occur at undiminished rates, in California and across the nation, despite decades of prevention efforts. Moreover, the number of people living with HIV is rising steadily, thanks to improved management of HIV infection. As a result, California, which ranks second in the nation in diagnosed cases of HIV infection, behind only New York, has identified 67,500 men, women, and children who carry the virus. (Estimates of the number of Californians who are infected but have yet to be diagnosed range as high as 33,513.) Not all of the state’s HIV-positive residents are currently on therapy, but eventually virtually all of them will be—and many of them will receive their drugs through government-supported programs. In addition, the longer these infected individuals live, the more likely they are to avail themselves of a range of support services that the state pays for. The drugs themselves, which are routinely administered in combination, are initially effective in suppressing viral replication in infected individuals, but their potency diminishes over time, even as the toxic effects of therapy accumulate. California, which is supporting the nation’s second-highest case-load of HIV-positive individuals, can expect to see that number grow at a rate of 5,000-7,000 a year for the foreseeable future. The cost of providing life-sustaining medications and social services to this burgeoning population will also continue to rise, not arithmetically but exponentially—because as increasing numbers of infected individuals fail standard drug regimens, it will be necessary to shift them to newer, more expensive treatments, and as the side effects of therapy become more manifest, it will be necessary to prescribe drugs to combat those toxicities, adding to the overall drug burden for patients and the overall cost of drug therapy for the state. In such circumstances, the prospect of stem-cell based therapy that will require “only a single treatment” is especially compelling. In theory, RNA interference might effectively cure individuals infected with HIV, by blocking the ports through which the virus enters CD4 cells and destroys the body’s immune system. And even if RNA interference proves only partially effective in blocking viral entry, it could significantly suppress viremia while sparing patients the toxicities associated with drug therapy. This would be a boon to infected individuals, but it would also be a benefit to uninfected Californians, because reductions in viremia in infected individuals translate into a reduction in the community burden of HIV infection—and that, in turn, reduces the overall rate of new infections statewide.
Progress Report: 
  • Our overall goal is to file an IND within 4 years for a hematopoietic stem cell based genetic therapy for HIV-1 disease. The concept is that introducing anti-HIV gene therapeutics into hematopoietic stem cells will produce a protected population of T lymphocytes and monocyte/macrophages (the cells specifically infected by HIV) in individuals to decrease viral load and maintain stable T lymphocyte counts. Hemapoietic stem cells are unique in that they are multipotent stem cells that give rise to all the types of blood cells, including T cells and monocytes/macrophages. During the first year we have met each of our key milestones and made significant progress in identifying and testing genetic reagents combined in the context of a lentiviral vector for stable delivery into hematopoietic stem cells. The vector candidates include combinations of gene therapeutics aimed at different stages of HIV replication namely: i) binding to the CCR5 HIV co-receptor (RNA interference to down-regulate CCR5), ii) fusion of the HIV virion to the cell surface (fusion inhibitor), iii) a restriction factor inhibiting translocation of the HIV genomic material from the cell surface to the nucleus (restriction factor) and, iv) inhibition of HIV expression within the cell (RNA interference directed to a key portion of HIV that drives its expression). We are presently identifying the optimal combination and vector/target ratio. We have also tested several reagents designed to increase transduction efficiency of hematopoietic stem cells and have validated assays to examine potential toxicity including genotoxicity of therapeutic vectors. Thus far, we have not seen any general vector-induced toxicity. In order for this gene transfer to be applied to patients, the hemapoietic progenitor stem cell transduction must be scaled up significantly. Experiments are currently in progress maximizing transduction of hemapoietic progenitor stem cells at sufficiently high cell numbers for future therapeutic analysis.
  • HIV-1 therapy requires combinations of reagents in order to effectively suppress HIV-1 replication. We have created several combinations of anti-HIV reagents through genetic engineering, which will eventually be delivered to humans through adult blood stem cells. We have compared the effectiveness and safety of these genetic “vectors” in cell culture and in an advanced mouse model, which allows human blood cells to grow in tissues. In addition, this mouse model allows one to investigate HIV-1 infection within the animals. Through these tests, we narrowed combinations down to those that seem to be the most effective based upon showing no toxicity and possessing the ability to be maintained within human blood cells in the mouse, and resist multiple strains of HIV-1 infection both in cell culture and in the humanized mice.

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