It’s difficult to believe there is anything that Star Wars can teach us about cell therapy, let alone cell therapy investment. However, in 2016 Tom Isaacs, then President and Co-founder of the Cure Parkinson’s Trust, drew parallels between the Star Wars narrative and attempts to use stem cells to cure Parkinson’s Disease. His words captured the imagination of several researchers and writers who have since used Star Wars to describe the science and success of Car T therapies for a range of diseases. It turns out when we look past the droids, blasters, and clones, there are several things Star Wars can teach us about cell therapy investment.
1. Within our own bodies are genetic materials that can be used for us — or against us. Whether we’re fighting the Death Star or having at it with lightsabers, it’s clear from Star Wars that our odds are much better when the Force is with us. In the case of disease, our genes and cells can work against us in ways reminiscent of the Dark Side.
Then again, if we can learn to harness their potential, the products of our genes and cells can make the Force Unleashed look like Luke’s first laughable attempts at using the Force on board the Millenium Falcon. The challenge for cell therapy investments is to maintain our belief in the power of Car T cells and immunotherapy as we work to make it a reality.
2. We must resist claims of a quick victory and focus on the results that come from sustained, scientific study. When Luke asks Yoda how he will know the good from the bad side of the Force, Yoda tells him “You will know… when you are calm, at peace, passive. A Jedi uses the Force for knowledge and defense, never for attack.”
In cell therapy investment, we must determine which approaches to fund and insist on research and trials that meet all clinical regulation and standards for objectivity and reproducibility. We need to follow up on any anomalies to our satisfaction as part of our due diligence. Star Wars teaches us that we must use our discretion to delineate between what is and what might be. Our hearts and our purpose must ultimately decide which gene and cell therapies will be able to sustain and perform well as an investment.
3. We want the numbers working with us. It was an awesome show of power when those rows and rows of clone troopers marched onto the transports as the Clone Wars began. It is equally as awesome to envision a time when we can equip the T cells that
are our personal army with what is needed to replicate and attack the cells that are making us ill. Another lesson Star Wars teaches us through the clone troopers is that, although the urge to run away or despair when faced with overwhelming defeat is more than reasonable, we can defeat those armies if we stand strong and fight back. For cell therapy investment, that means using biotechnology to create our own armies to cure disease by using power for its best purpose. In short, we want the clone troopers on our side.
4. Success is a process, not an event. In their 2018 paper, Cell-based therapy for Parkinson’s disease: A journey through decades toward the light side of the Force, the authors write about “A new hope–fetal cell trials” and a stem cell therapy study that was deemed a failure at first. “New and previously unknown Jedi(s) suddenly appear and give the impression that the future looks much more promising than ever,” they write. Similarly, when viewed in a new way, a stem cell therapy that was deemed a failure was recognized as a source of a new hope. The authors’ write, “In a similar way, cellular reprogramming has revolutionized medical sciences by allowing large-scale studies of
patient-specific cells including those of the nervous system, and with that, a new and previously unconsidered source of cells for therapy is emerging.” For cell therapy investors this points to the tantalizing possibility that a “failed” attempt may have a new possibility as science progresses. While these authors wrote of stem cell therapy, the same persistence is imperative for those creating T cell therapies. After all, even with the Force, it took several tries for the Dark Side to be defeated.
5. We must remain open to possibilities. The goal is to keep moving toward the Light Side of the Force, doing what we can to advance the technology that will bring us to full utilization of its power. We cannot rush down the quick and easy path, discarding whatever doesn’t work immediately. Some of the things discovered along the way may have important uses of their own; they may be worth a second look.
After all, when we first met Yoda, few guessed he was a Jedi Master.
Bottom Line:
When all is said and done, Star Wars provided some valuable lessons for cell therapy investors – without being heavy-handed. The narrative highlighted the fact that we have within ourselves the genetic material and cells that can harm us — or cure us. It depends upon our perspective and where we invest our time and talents. Star Wars showed us that the quick wins are not the wins that rule the day; steady progress toward a goal with integrity in the process is what it takes.
When there are millions of anything — clone troopers, whatever — we want those millions of things to be working to our advantage. When we try something brilliant and it fails the first time, we can abandon that idea or settle down to ascertain its potential in another area. Not everyone is going to be a crack shot; someone also needs to hold off the naysayers until the shot is taken. After all, where would Luke have been without Red Leader? And finally, as a cell therapy investor, it’s necessary to stay the course while being informed and curious about what is next in the pipeline as well as what seems to have failed and what is just the start of an idea. Fetal cells? Bone marrow? Reprogrammed cells? Somewhere in the mix, in life as in Star Wars, lies success.
Read more:
Cell Therapy is Creating the Next Generation Cures for Cancers
Cell Therapy Companies in Maryland
Published on AGT
Maryland is home to one of the largest life science clusters in the United States with more than 500 biotech companies. In addition to several state-of-the-art labs, Maryland is home to the NIH in Bethesda. Research opportunities, as well as BS and MS degree programs, are offered at Johns Hopkins in Baltimore and the University of Maryland in College Park. Montgomery College in Germantown offers the AAS degree and certificate programs in biotech. World-class training by companies like BioTrac and Biotech Primer attracts an international audience of professionals.
Maryland’s cell therapy biopharma companies working with gene and cell therapies are revolutionizing drug discovery and drug development as they create the next generation of medicine. These biopharmaceutical companies make use of a variety of healthy cell types to develop therapies to repair or replace damaged cells in a patient’s body. Here is the latest news from seven of these cell therapy companies.
In February 2020, WindMil announced a collaborative pre-clinical research partnership with the University of Pennsylvania (Penn) to explore novel chimeric antigen receptor (CAR)-engineered MILs (CAR-MILs™) in hematological and solid tumor model settings. The collaboration will leverage WindMIL’s and Penn’s respective expertise to conduct pre-clinical comparisons of the characteristics and functionality of CAR-T and CAR-MIL products.
WindMil Therapeutics is a private clinical-stage company developing a novel class of autologous cell therapies based on marrow-infiltrating lymphocytes (MILs™) for cancer immunotherapy. WindMIL uses its novel insights in bone marrow immunology to create life-saving cancer immunotherapeutics for patients. Their proprietary process activates and expands these cells and offers immunotherapeutic advantages that are unique. These advantages include inherent tumor-specificity, high cytotoxic potential, and long persistence.
Located: Baltimore
Product: Unmodified MILs and CAR-MILs
Long-Term: To translate novel insights in bone marrow immunology into life-saving cell therapies for cancer patients.
In June 2020, MaxCyte, the global clinical-stage cell-based medicines and life sciences company, announced the launch of the first product in the new and expanded range of ExPERT™ disposables. The new R-1000 cuvette can process a volume of up to 1 mL, or up to 200 million cells, and provides increased versatility for companies developing cell therapy drugs as well as those advancing early drug discovery. This expands the company’s range of disposables and provides additional growth opportunities by addressing one of the processing volumes frequently requested by customers. Based on extensive customer feedback, this new design can be used across the complete range of MaxCyte’s electroporation instrumentation, including the recently launched ExPERT ATx™, STx™ and GTx™, and represents the first product in a new industrial design that provides improved usability and handling.
Maxcyte is focused on accelerating the discovery, development, and manufacturing of cell-based medicines to address a range of acute and chronic diseases. Their partners in biopharma will create new cell therapy medicines through the use of MaxCyte’s ExPERT platform. MaxCyte also has a proprietary mRNA-based therapeutic platform for autologous cell therapy. These CARMA therapies can be used to create treatments for solid cancers.
Symbol: MXCT (NASDAQ)
Located: Gaithersburg
Product: Flow Electroporation® Technology, ExPERT Platform
Long-Term: To accelerate the development of cell-based treatments such as small molecule drugs, biologics, vaccines, and cell and gene therapies to address a range of acute and chronic diseases.
In October 2020, Precigen announced US Food and Drug Administration (FDA) clearance and successful technology transfer for its UltraPorator™ system, an exclusive device and proprietary software solution for the scale-up of rapid and cost-effective manufacturing of UltraCAR-T® therapies. The FDA cleared UltraPorator as a manufacturing device for clinical trials of Precigen’s investigational UltraCAR-T therapies in compliance with current good manufacturing practices (cGMP). In addition, the team has successfully completed technology transfer of the UltraPorator system for the manufacturing of UltraCAR-T in the ongoing clinical trials for PRGN-3005 in ovarian cancer at the University of Washington/Fred Hutchinson Cancer Research Center and for PRGN-3006 in acute myeloid leukemia (AML) at the Moffitt Cancer Center.
Precigen’s approach to the design of potent on-target gene and cellular multifunctional therapies is accomplished through the use of their design approach. This disciplined approach uses viral and non-viral suppression systems, genome, DNA, RNA, and protein engineering, with a suite of precision bioengineering switch technologies to control gene expression and regulation to deliver therapies with improved safety and efficacy.
Symbol: PGEN (NASDAQ)
Located: Germantown
Product: PRGN-3009, PRGN-3010, PRGN-2012
Long-Term: To discover, develop, and commercialize next-generation gene and cell therapies focused in immuno-oncology, autoimmune disorders, and infectious diseases.
In October 2020, NexImmune announced that it had signed a research initiative related to its AIM nanoparticle technology with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes, and other life-threatening diseases. City of Hope is a participating clinical site in the ongoing Phase 1/2 study of NEXI-001. The cancer center will leverage both patient samples from the ongoing NexImmune Phase 1/2 clinical study of NEXI-001 in acute myeloid leukemia (AML) patients with relapsed disease after allogeneic stem cell transplantation and the center’s tumor repository bank of primary leukemia samples, one of the largest collections in the world, to drive the research. NEXI-001 is a cellular product candidate that contains populations of naturally occurring CD8+ T cells directed against multiple antigen targets for AML, and it is the first clinical product generated by the company’s AIM nanoparticle technology.
NexImmune is a private clinical-stage biotechnology company. The company develops unique non-genetically-engineered T cell immunotherapies through the use of its Artificial Immune Modulation (AIM) proprietary technology. The modular design of the AIM platform enables rapid expansion across multiple therapeutic areas, with both cell therapy and injectable products. NexImmune’s pipeline has preclinical programs, including cell therapy and injectable product candidates, for the treatment of oncology, autoimmune disorders, and infectious diseases.
Located: Gaithersburg
Product: NEXI-001, NEXI-002, NEXI-003
Long-Term: To harness the power of precision technology to restore natural immunity in the treatment of life-threatening diseases.
In November 2020, AGT announced that the first trial participant was enrolled in the Phase 1 trial of AGT103-T, a new cell and gene therapy for HIV disease. The first trial participant underwent leukapheresis, a procedure for obtaining concentrated white blood cells, which will be used for manufacturing the AGT103-T cell product. After manufacturing and required safety testing, the product will be infused back into the trial participant to test the safety and its effect on HIV. Phase 1 is in the Maryland/DC Area.
American Gene Technologies is a private biotechnology company dedicated to finding cures and treatments for infectious diseases, cancers, and monogenic disorders. AGT uses cell and gene therapy in its work. Their current research programs use modified T cells for a prospective functional HIV cure, lentiviral based gene therapy for a PKU cure, and immuno-oncology program that targets cancerous solid tumors.
Located: Rockville
Technology: Rapid lentiviral vector gene delivery platform
Long-Term: To leverage the power of gene and cell therapy to reduce human suffering or early death from serious human diseases.
In June 2020, Autolus Therapeutics announced preclinical data related to AUTO5 in T cell lymphoma and AUTO6NG in small cell lung cancer, as well as an oral presentation related to AUTO7 in prostate cancer at the American Association for Cancer Research (AACR) Virtual Annual Meeting II on June 22 – 24, 2020. “Behind our lead programs AUTO1 in ALL and AUTO3 in DLBCL, we have a number of exciting preclinical product candidates progressing towards the clinic,” said Dr. Christian Itin, chairman and chief executive officer of Autolus. “These data updates for AUTO5, AUTO6NG, and AUTO7 illustrate the strength of our broad and modular cell programming technology to adapt the product properties to the specific tumor type.”
Autolus Therapeutics is a clinical-stage biopharmaceutical company founded on advanced cell programming technology. It is a leader in T cell programming and manufacturing technology. The company works with physicians and other healthcare providers to extract immune cells from patients, equip them with a receptor that targets the cancer cell, and infuse the patient’s modified cells back into the patient. Autolus believes its immuno-oncology therapies will offer cancer patients clear benefits over existing treatments.
Symbol: AUTL (NASDAQ)
Located: Rockville
Product: AUTO1
Long-Term: To bring life-changing treatments to cancer patients by reprogramming their own T cells to combat hematological malignancies and solid tumors.
In November 2020, Arcellx announced that clinical data from its ongoing Phase 1 Study of CART-ddBCMA, a genetically engineered cell therapy utilizing the company’s novel synthetic binding domain for the treatment of patients with relapsed and refractory multiple myeloma, will be presented at the 62nd American Society of Hematology (ASH) Annual Meeting, taking place virtually Dec. 5-8, 2020. CART-ddBCMA is a Phase 1 study of Arcellx’s BCMA-specific CAR-modified T-cell therapy utilizing the company’s novel BCMA-targeting binding domain for the treatment of patients with relapsed and refractory multiple myeloma
Arcellx is a private clinical-stage biopharmaceutical company. It develops noble, adaptive, and controllable cell therapies for the treatment of patients with cancer and autoimmune diseases. Arcellx’s paper, “Chimeric Antigen Receptors Incorporating Novel (non-scFv) Binding Domains Targeting CD123 Direct Potent Antitumor Activity of T Cells: Correlation Between Affinity and Activity” was presented at the American Association for Cancer Research (AACR) 2020 Virtual Annual Meeting II.
Located: Gaithersburg
Product: CAR T-Cell Therapy for the treatment of cancer
Long-Term: To bring ARC-sparX platform cell therapies to millions of patients who can self-administer prescribed sparX proteins under the care of academic and community practices.
In September 2020, RoosterBio announced it had entered into a Cooperative Research and Development Agreement (CRADA) with The Geneva Foundation (Geneva), a non-profit dedicated to advancing military medicine, and the Uniformed Services University of the Health Sciences (USU), an institution of higher learning within the United States Department of Defense (DoD) on behalf of USU’s 4 Defense Biotechnology, Biomanufacturing, and Bioprinting Center (4D Bio3). Under the terms of the CRADA, RoosterBio will support biofabrication in austere environments and provide subject matter expertise in Ready to Print (RTP) technologies.
RoosterBio is radically simplifying the use of adult human mesenchymal stem/stromal cells (hMSCs) in order to propel the commercialization of regenerative technologies. Their living cellular technologies are more affordable, easier to access, and much simpler to incorporate into product development efforts than the current time-consuming and costly technologies. This will lead to a rapid acceleration in products that incorporate these technologies coming to market.
Located: Frederick
Product: an industrialized supply chain of high-quality hMSCs
Long-Term: To incorporate MSCs into technology pipelines to drive a tremendously positive impact on human healthcare.
Located: Gaithersburg
Product: CAR T-Cell Therapy for the treatment of cancer
Long-Term: To bring ARC-sparX platform cell therapies to millions of patients who can self-administer prescribed sparX proteins under the care of academic and community practices.
Published on AGT
Approximately 7,000 rare diseases affect 350-500 million people worldwide. The majority of these (80%) are monogenic, so-called because these genetic disorders are caused by a mutation in a single gene. While gene therapy holds great promise for the treatment of monogenic diseases in the future, efforts to find cures to date with traditional pharmaceuticals have resulted in treatments for only 5% of all rare diseases. Why has it been so difficult to find rare disease cures?
Difficulty in Diagnosis
Before the Human Genome Project (HCP) was completed in 2003, researchers did not have access to the complete genome of our species. Without this knowledge, it was impossible to arrive at an accurate diagnose of the cause of a genetic disease; the best that could be done was to attribute the symptoms to a type of disease based on its characteristics. Once that was done, there might be treatments that would help with the symptoms, but there would be no cure. With the use of genetic testing, it is now possible to identify the exact location of the defective gene. Even with the resources available to us today, it still takes time to make a diagnosis, as was the case with SLC-6A1 and Amber Freed’s son, Maxwell, which we wrote about here.
Small Patient Population
The exact definition of a rare disease varies by country, but no matter the definition, rare diseases affect 1% or less of the global population. Since there are many rare diseases within that 1%, the population for any one disease is very small. Because those affected are located around the world, they are unknown to one another or to those conducting rare disease research. The geographic spread, combined with the small number of people affected, has made it difficult to gain recognition as a population in need of a cure.
The National Organization for Rare Disorders (NORD) has created a site with resources that include information on more than 1,200 diseases and a listing of clinical trial and research studies by disorder. NORD is making it possible for those with rare disorders to work together to advocate for themselves because “Alone we are rare. Together we are strong.”Ⓡ The use of technology to make remote participation possible in research and clinical trials, as described in our article, Treatment of Rare Diseases: What You Need to Know, is also a potential game-changer.
Profitability
Any company sets out to earn a profit on the products it creates. The company needs to clear a profit overall if it is to remain viable. As we discussed in Treatment of Rare Diseases: What You Need to Know, the argument has long been that the cost of research and development for these rare conditions is prohibitive and the patient population small. There was no way for the pharmaceutical industry to profitably produce new treatments.
The financial benefits for pharmaceutical companies working on treatments for orphan diseases through the Orphan Drug Act are explained more fully in our article, Benefits of FDA Orphan Drug Designation: What You Need to Know. These benefits are making a difference in the profitability equation. As a result, firms like American Gene Technologies (AGT) are pursuing disorders like Phenylketonuria (PKU) with the use of an Orphan Drug Designation.
Show Me the Cures
1. Sickle Cell anemia affects about 100,000 people in the United States and millions worldwide. Until last year, the only possible cure was a stem cell transplant. However, since there is the risk of graft vs host reaction with a stem cell transplant, it wasn’t considered a viable cure. All of that changed in March 2019 when Janelle Stephenson, 28, received a genetic treatment as part of an NIH clinical trial. The replacement of the single defective gene, the beta-globin gene, made it possible for Stephenson’s cells to produce anti-sickling hemoglobin. Her cure is believed to be one-and-done: one in which there is no need for ongoing treatment.
2. Phenylketonuria (PKU) affects various ethnic groups and geographic regions worldwide. In the United States, it occurs in 1 in 10,000 to 15,000 newborns. All newborns are tested for PKU within 72 hours after birth with a simple heel prick to generate the small amount of blood needed for the simple test for PKU. It is essential to identify those infants at risk for PKU, so that they can be started on an effective treatment and eat a diet that limits foods containing phenylalanine during infancy. As they grow older, they must avoid foods that are high in protein. Failure to follow these guidelines results in intellectual disabilities caused by a buildup of the amino acid phenylalanine, which is toxic to the nervous system. There is currently no cure for this debilitating disease, although American Gene Technologies (AGT) is working toward a cure for PKU.
3. Cystic Fibrosis affects about 30,000 in the United States. and more than 70,000 people worldwide. Until recently, attempts to deliver a working copy of the gene necessary to a cure have not been effective. With advances in viral vectors, this is changing. In 2019, the Cystic Fibrosis Foundation announced $500 million in funding over the next six years for research into treatments for cystic fibrosis. These include gene therapy strategies.
4. Hemophilia A affects an estimated 400,000 males worldwide, with about 20,000 in the United States. There is currently no cure for this genetic disease. In August 2020, the U.S. Food and Drug Administration (FDA) rejected a gene therapy called Roctavian and asked BioMarin Pharmaceutical for more evidence that the treatment is durable enough to justify use in patients by proving a long-lasting effect on bleeding rates that will not wear off, resulting in a return to the current standard of care for patients.
5. Muscular Dystrophy (MD) The most common forms in children, Duchenne and Becker, affect approximately 1 in every 5,600 to 7,700 males ages 5 to 24. There is currently no known cure for this genetic disease. However, the use of CRISPR gene-editing technology may lead to a long-awaited cure or treatment options.
Bottom Line
The outlook for rare disease cures is excellent. The ability to make a diagnosis sooner rather than later gives those with the disease more time to identify and participate in promising research and trials. Information such as that on NORD’s site, along with a diagnosis that pinpoints the specific gene needing repair in monogenic disorders, makes it possible for people around the world to connect and form patient advocacy groups to work for a cure. Remote participation in research and trials means that people with rare diseases can participate from wherever they are located, and Orphan Drug designation brings financial incentives for the creation of cures for small populations of patients. Today, we are already seeing movement toward a cure in some of the most well-known rare diseases as all of these factors combine with advances in gene and cell technology. The improvement of vectors and the use of CRISPR will likely lead to more.
Take Away
American Gene Technologies is committed to developing genetic therapies that will enable those with PKU to lead normal lives. The FDA granted AGT an Orphan Drug Designation in 2018. This designation provides AGT with eligibility for tax credits, market exclusivity for 7 years post-approval, and the waiver of new drug application fees totaling more than $2 million in cost savings. Today, AGT PKU Cure Program is in the pre-clinical validation stage.
Published on AGT
A new immune deficiency illness came on the scene in 1981. In the years immediately following, four questions arose that indicated the uncertainty of the time: What was this illness? How was it transmitted? Could it be treated? Could it be cured? By 2004, when the number of people living with what we now knew as HIV had risen to its highest level, three of those questions had been answered: The illness was a retrovirus. Transmission occurred most commonly through sexual behaviors and needle or syringe use. A daily cocktail (combination) of antiretroviral therapy (ARTs) could stop HIV from progressing to its deadly form (AIDS).
Today, the daily use of ARTs for HIV treatment has made what was once a death sentence into a chronic illness. Yet, prolonging the life of those infected is not a cure. As the search for an HIV cure continues, four new questions related to the search have arisen: Is a cure possible? Are there viable cure strategies? Do we still need a cure? Are we any closer than in 2004?
Is a Cure Possible?
There are two cases in which HIV-infected individuals have been cured. Both cures were achieved as the result of treatment for a condition other than HIV. The first cure was announced in 2008. The first person, Timothy Ray Brown aka the “Berlin Patient,” had received two bone marrow transplants to treat acute myeloid leukemia (AML). The stem cells were from a donor who had inherited the same alleles for the CCR5–Δ32 mutation. The authors of a 2017 peer-reviewed article in BioMed Research International, Advancements in Developing Strategies for Sterilizing and Functional HIV Cures, wrote that the CCR5–Δ32 mutation “renders cells highly resistant to HIV-1 infection.” The authors continued, “Eight years after treatment, he “appear[ed] to be free of both HIV and AML. However, it is very difficult to find donors with human leukocyte antigens (HLA) identical to those of recipients for CCR5–Δ32 stem cell transplantation, while the mortality rate of transplant surgery is up to 30%.” It is this mortality rate, as well as the possibility of host vs. graft disease that makes stem cell transplants an unrealistic avenue for an HIV cure.
Are There Viable Strategies?
Webster’s Dictionary defines cure as “a healing or being healed; restoration to health or a sound condition.” It mentions nothing about the strategy for achieving a cure. Two strategies for a cure today are sterilized and the functional cure. With the sterilized cure, all traces of HIV are absent; No disease remains in the patient, in a latent reservoir or otherwise. With the functional cure, modified receptors protect cells from HIV infection; The infection is still present, but it is present at levels below detection or transmission. In Advancements in Developing Strategies for Sterilizing and Functional HIV Cures, the authors identify the key obstacle to an HIV cure as the latent HIV reservoirs, mainly composed of resting CDR+ T cells in the early stages of HIV infection. The figure below illustrates the sterilized cure (a) in which the HIV reservoirs are eradicated, and there is “the complete elimination of replication-competent proviruses.” “Functional cure refers to the long-term control of HIV replication, which involves maintaining a normal CDR+ T cell count and HIV replication below a detectable level,” represented by (b) with the prevention of susceptible cells from HIV infection.
A third strategy is described in an article at NIH/NIAID, Sustained ART-Free HIV Remission. Sustained ART-free remission would not involve eradicating the HIV reservoir but would allow a person living with HIV to keep the latent virus suppressed without daily medication. Most approaches under investigation include altering the immune system to induce long-term control of HIV. Researchers are attempting to achieve their goal by manipulating the immune system with interventions that target HIV and HIV-infected cells or change the behavior of immune cells as they try to address the infection more effectively.
Do We Still Need a Cure?
The widespread use of ARTs to control HIV infection makes it possible for those who would have died within eight to ten years of an HIV diagnosis to live for decades. This reality leads some to question the need for a cure. Wouldn’t HIV prevention be sufficient? The question is a good one, however, living with HIV is not the same as having a cure for HIV. ARTs are a toxic cocktail of drugs, which must be taken every day, with long term side effects including heart disease, diabetes, kidney disease, and bone wasting. This reality leads others to question how we can not pursue a cure.
The role played by ARTs cannot be overlooked. Their daily use by millions of infected people has reduced the number of new infections across the population since their global use began in 2010. Yet, there were still 1.7 million people newly infected in 2018 worldwide. In the East and Southern African countries lacking adequate healthcare or health-related information, they still average 2,000 new cases each day. Millions of children have lost one or both parents to this disease with no end in sight.
To stem the tide of HIV infection, UNAIDS has instituted its 90-90-90 targets. Since the stigma of HIV diagnosis leaves people reluctant to be tested – a fatal misstep since there is no treatment without a diagnosis – the first of the UNAIDS targets addresses this directly by calling for widespread testing to make 90% of the population aware of their HIV status. The next target is for 90% of those with an HIV diagnosis to receive treatment with ARTs. The final target is for transmission of the virus to be suppressed through the daily use of ARTs in 90% of those treated with ARTs.
The ability to prolong the lives of the 37 million people already infected with HIV/AIDS while reducing transmission of the virus meets the goal of limiting new infections. Perhaps it will even lead to the eradication of the virus for all practical purposes. However, to improve the quality of their lives requires a cure.
Are we any closer to a cure than we were in 2004?
Researchers are pursuing several strategies. As a result of the London Patient’s cure, some researchers are capitalizing on the use of stem cells from those naturally resistant to HIV. A strategy along a similar path uses antibodies from the same “elite controllers.” A third possibility is the “kick and kill” strategy in which the latent virus is first awakened and then killed. “Latently infected cells appear identical to uninfected cells, so there is no way [for the body] to distinguish between the two,” said Professor John Frater of the University of Oxford in a 2019 article in The Guardian. “But if those cells start to express viral proteins on their surface, they become a target.” Advances in research have brought about additional possibilities with existing strategies while bringing us closer to a cure.
Conclusion
We now have answers to the four questions related to our current pursuit of an HIV cure. Yes. Researchers have seen that a cure is possible. Yes. There are at least two viable strategies, as well as the possibility of sustained ART-free remission. Yes. We still need a cure because ARTs are to those infected with HIV as insulin is to those with diabetes. Only a cure will make it possible for those infected with HIV to lead a normal life. Yes. We are closer to a cure than we were in 2004.
Take away:
Could AGT have the Long-Awaited Cure?
American Gene Technologies (AGT) is determined to restore active HIV immunity to individuals infected with HIV. To that end, they have developed a promising approach. In 2016, AGT met with the FDA to propose a new approach for treatment.In 2019, AGT submitted an Investigational New Drug (IND) application to the FDA, seeking approval to begin a human trial.
In 2020, NIAID repeated AGT’s approach to a functional cure for HIV/AIDS.. Researchers at NIAID were able to replicate AGT’s results. Their findings are documented in a peer-reviewed article co-authored by AGT and published in the May issue of Molecular Therapy. AGT recently began its Phase 1 study. The clinicaltrials.gov identifier number is NCT04561258 and the study ID is AGT-HC168. For information about the ongoing Phase 1 study of AGT103-T, and information on the trial sites, click here.
AGT Founder and CEO Jeff Galvin describes what AGT’s trial will accomplish as “isolating HIV T-cells in somebody’s body to make them immune to HIV…. I’m improving the function of those cells, so they’re able to clear HIV without becoming infected, just the way your cold T-cells can clear a cold without becoming infected by the cold, which is the key to clearing this pathogen? It’s that simple.”
Visit the interactive timeline.
Learn more about the history of HIV/AIDS
Read more about the work toward an HIV Cure
Published on AGT
In the forty years since the HIV/AIDS pandemic began in 1981, researchers have learned a lot about this disease that destroys the immune system. Early on, they identified the method of transmission and the means of HIV replication. They went on to successfully turn what had been a deadly disease into a chronic illness through the daily use of antiretroviral drugs for the treatment of HIV. (See The History of HIV Cure Research: Discovery to Treatment to read more.) The use of daily antiretroviral therapy (ART) slowed the rate of new infections since ARTs were made available for use on a global scale. The “Berlin Patient” in 2008 and the “London Patient” in 2019, proved a sterilized cure in which no trace of the virus is left, was possible when they were cured of HIV through the use of stem cell transplants. In 2015, UNAIDS called for the eradication of the virus through the daily use of ARTs to achieve undetectable levels of the virus in 90% of those who are HIV-positive and using HIV medication. Today, the HIV pandemic is still far from over. There is an effective treatment, but still no cure for the 38 million people living with HIV worldwide and those who will be infected in the years to come.
A functional HIV cure has the greatest chance of success
The two patients cured to date were cured with a sterilized cure. A functional cure is another HIV cure strategy. The end result of either is a patient without HIV/AIDS. Yet, the path to the cure is very different:
- Sterilizing Cure: A Treatment where the replication-competent HIV provirus is completely eliminated from the body. With this type of cure, there would be no concern about latency. However, at this time, a sterilized cure is only possible if the HIV-positive person’s immune system is “wiped clean” and restarted with new bone marrow. In the case of the “Berlin” and “London” patients, stem cell transplants were used to cure them of blood cancers. The transplants made use of bone marrow from CCR5–Δ32 donors. These donor cells had a mutation that “renders cells highly resistant to HIV-1 infection,” according to a 2007 peer-reviewed article in BioMed Research International. The transplants cured the patients of both their blood cancers and HIV, proving that a sterilized cure is possible. The article states that “However, it is very difficult to find donors with human leukocyte antigens (HLA) identical to those of recipients for CCR5–Δ32 stem cell transplantation, while the mortality rate of transplant surgery is up to 30%.” The possibility of a host vs. graft reaction, in conjunction with the 30% mortality rate, makes bone marrow transplant surgery a poor route to a cure and it is not being pursued at this time.
- Functional Cure: A treatment where there is durable suppression of viral replication in the absence of antiretroviral therapy. The viral load in a functional cure will permanently remain below the level at which it is possible to either infect others or for the patient to become infectious again from their own viral reservoir. The patient will not progress to AIDs and may be immune to re-contracting the virus from others. The current preference is for a functional cure.
Biopharma holds the promise of a functional cure for HIV through immunology.
Biopharma works with a person’s cells and genes to effect a cure. Rather than make use of toxic drugs with damaging side effects and the necessity of ongoing treatment, gene and cell therapy “updates” the patient’s immune system to fight the virus in the same way that computer software is updated. Jeff Galvin, AGT CEO explains the rationale behind using viruses to fight themselves in this way, “think about this in terms of your computer. We convert those [human] viruses to updates. In other words, we take these things that will invade your body, and reprogram your cells to do all sorts of horrible things – we’re talking about not just colds and cases of flu, but HIV infection. The virus goes into your body, reprograms your cells, and takes over your body over time. But we can go ahead now and split open these deadly viruses, pull out the viral DNA, and put in whatever DNA we want. These are little software updates to the organic computer that is the human cell.” Given biotech’s ability to “reboot” the human operating system through the use of cell and gene therapy, researchers are focused on a functional cure.
Biopharma is ideally suited to creating a functional cure. Researchers will pull out the HIV DNA from a patient’s cells and use those cells in an autologous cure, i.e., use the patient’s own cells. Once they remove the infected cells, researchers prep them and reintroduce these “updated” cells through infusion. To produce a functional cure for HIV/AIDS, lentiviral vectors can be used in a single-dose. Ideally it will be one-and-done: The patient would be cured, with no additional treatments and no need for the ongoing use of ARTs.
Pauza Presentation
In his August 31st presentation at the Advanced Therapies Congress & Expo 2020, AGT’s Chief Science Officer David Pauza spoke about the latest research in cell and gene therapy for immunotherapy to create a functional cure for HIV. In his remarks, he not only touched on the work being done by AGT on AGT103-T but also noted the way in which AGT examined the work done by others in the field in order to spot strengths and deficiencies in their approaches.
Previous Research
A review of previous HIV gene therapy studies to spot strengths and deficiencies highlighted some basic features in common.
In short, it was common for researchers in previous HIV cure studies to:
- extract PBMC (peripheral blood mononuclear cells) from the patient and expose them outside the body to agents that could modulate or delete the CCR5.
- target PBMC (leukapheresis) and multipotent CD34+ bone marrow hematopoietic precursor (progenitor) cells.
- use viral vectors such as lentivirus, retrovirus, and adenovirus, or naked RNA transfection, to introduce the desired gene therapy.
- achieve improved acceptance of the cells by reduced-intensity conditioning with a low dose of a chemotherapy drug that works by slowing or halting cell growth.
AGT103-T Process
AGT103-T is a cell and gene immunotherapy for HIV disease. It may achieve a functional cure when delivered in a single dose through an infusion. “This product is designed to reinvigorate the host immune response to HIV,” said Pauza, “to create a natural response that’s capable of attacking HIV and resolving it in much the way we do for many other viral diseases.” Gag-specific (HIV-specific) CD4 T cells are a population of T cells that is depleted early in HIV disease. They are an essential component of a healthy immune system and are not recovered despite prolonged therapy.
AGT103-T is designed to reinvigorate and support a potent antiviral immune response by:
- Reconstituting the Gag-specific CD4 T cells through the infusion of a highly enriched, autologous cell product. These group-specific CD4 T cells are essential to most immunological functions. It is the depletion of this subset of T cells that is responsible for the destruction of the immune system in HIV-positive individuals. Replenishment of the supply of these CD4 T cells is essential if the immune system is to function properly.
- Engineering Gag-specific CD4 T cells to resist HIV infection and inhibit HIV release from latently-infected cells. This is a necessary step because it is not enough to replenish the supply of healthy T cells; the new cells must be able to resist infection and keep cells in the HIV reservoirs from releasing latent HIV. Pauza said, “We engineer T cells in this product to resist HIV infection themselves. This makes them more durable once we place them back in the body and also prevents them from releasing HIV if they were part of the viral reservoir. Our hope is that this product will restore the capacity of generating a natural cytotoxic T cell response and also may promote more rapid evolution and production of neutralizing antibodies.”
- Restoring the capacity for generating cytotoxic CD8 T cell neutralizing antibodies. CD8 T cells are a critical subpopulation of T cells. They act as a go-between for adaptive immunity, and cytotoxic T cells are essential for killing HIV-infected cells. Further, the gag-specific CD4 T cells should work with B cells to make neutralizing antibodies.
Successful Manufacturing Process
The results from AGT103-T are encouraging. By enriching Gag-specific CD4 T cells (a departure from previous HIV gene therapy studies that were reviewed) AGT achieved approximately 1 billion Gag-specific CD4 T cells from a starting point of 1 million Gag-specific CD4 T cells. It is anticipated that infusing these 1 billion cells will increase the total count in the patient by more than 10 times. This should support normal immunity against HIV, resulting in the desired functional cure.
Next Steps
AGT is pursuing reconstitution of the immune system rather than replacement of genetically engineered, bulk CD4 T cells. The reconstitution method is used to overcome a key immunological defect by infusing an enriched cell population. In the case of HIV, the defect is irreparable loss of HIV-specific CD4 T cells and the failure to recover these cells despite prolonged antiretroviral therapy.
When compared with the SB-728-T (Sangamo Biosciences) study that used zinc finger nuclease anti-CCR5, AGT103-T’s use of the lentivirus vector LV AGT103 returned 2,000 times the dose of Gag-specific CD4 T cells depleted more completely of CCR5. Specifically, where SB-728-T delivered ~ 3.5×105 Gag-specific CD4 T cells, AGT103-T delivered ~ 8.5×108 Gag-specific CD4 T cells. The next step is for AGT to test AGT103-T in a clinical setting.
Take away:
American Gene Technologies (AGT) is determined to restore active HIV immunity to individuals infected with HIV. To that end, they have developed a promising approach. In 2016, AGT met with the FDA to propose a new approach for treatment.In 2019, AGT submitted an Investigational New Drug (IND) application to the FDA, seeking approval to begin a human trial.
In 2020, NIAID repeated AGT’s approach to a functional cure for HIV/AIDS.. Researchers at NIAID were able to replicate AGT’s results. Their findings are documented in a peer-reviewed article co-authored by AGT and published in the May issue of Molecular Therapy. AGT recently began its Phase 1 study. The clinicaltrials.gov identifier number is NCT04561258 and the study ID is AGT-HC168. For information about the ongoing Phase 1 study of AGT103-T, and information on the trial sites, click here.
AGT Founder Jeff Galvin describes what AGT’s trial will accomplish as “ isolating HIV T-cells in somebody’s body to make them immune to HIV…. I’m improving the function of those cells, so they’re able to clear HIV without becoming infected, just the way your cold T-cells can clear a cold without becoming infected by the cold, which is the key to clearing this pathogen? It’s that simple.”
Visit the interactive timeline.
Learn more about the history of HIV/AIDS
Read more about the work toward an HIV Cure
Published on AGT
Photo courtesy of Kazia Therapeutics.
BioSpace recently spoke with Dr. James Garner, CEO of Kazia Therapeutics, an oncology company that is focused on the development of cancer drugs. The company is publicly listed both in Australia and on NASDAQ in the U.S. Its lead program, paxalisib, is being developed to treat glioblastoma, the most common and aggressive form of primary brain cancer in adults.
Q: We last spoke in January about Kazia’s business model and the challenge of drugs crossing the blood-brain barrier to treat glioblastoma. Today, I’d like to talk more specifically about you. Let’s start with a simple one: What is your role at Kazia?
A: I’m the Chief Executive Officer at Kazia. That’s my job title if you like, but we’re a really small company and, like in most small companies, the job involves you to be involved with multiple areas of the business. I might spend a period of time in the morning talking to a clinician about a new clinical study, which is a very scientific, detailed discussion about how to answer a research question. Next, I might converse with an investor about company performance, explaining that their capital is in good hands and the potential for return on investment. In the afternoon, I could review the draft accounts for release to the S.E.C. because this is a listed company. So, it’s really a variety of different initiatives. It’s very much a Jack-of-all-trades role, which I think is part of the fun.
Q: How did you choose to work in biopharma?
A: As with most of the best decisions, it was made by accident. I trained as a medical doctor and studied in London at Imperial College. Coming from a medical family (both my parents and one of my grandparents are doctors) there was almost a sort of inevitability that I would go into medicine. I really enjoyed it, and I practiced for a few years in both the UK and Australia. Once you become a physician, medicine takes over your entire life. But I always knew there were other things I was very interested in pursuing. One of those areas was business in general. I took time out, earned an MBA, and worked for a few years at a consulting company. Eventually I started to put all of these career pieces together and found myself in the drug development industry. That’s where I’ve been ever since.
Q: What experience have you had in this the biopharma industry?
A: I’ve been fortunate to gain experience between multinationals and smaller biotech companies in the pharmaceutical industry. I’ve probably spent about 50% of my career in smaller, more biotech-style companies and the other half in large multinational companies. Many professionals prefer life with a big multinational because of the structure and extensive resources. Other professionals like working at smaller organizations. To be honest, I’ve always enjoyed both. I’ve been fortune having the opportunities to move back and forth between the two spectrums of the industry.
Q: Kazia is working to develop paxalisib to treat glioblastoma. Are there any other benefits that have come out of this research?
A: Our main focus is a disease called glioblastoma, which is the most common and aggressive form of brain cancer. Both John McCain and Beau Biden passed away from glioblastoma. However, we are also working on other forms of brain cancer. There is a childhood brain cancer called DIPG, or diffuse intrinsic pontine glioma. It’s a horrible rare disease which affects maybe four or five hundred kids a year in the U.S. It typically affects kids between the ages of 4 to 12 years. It is uniformly fatal, with a life expectancy from diagnosis of about 9 to 10 months. Currently, there are no FDA-approved treatments, but we’ve been trying to develop our drug for DIPG in parallel with our glioblastoma work. The FDA recently awarded us a Rare Pediatric Disease Designation for DIPG. This designation helps us in various ways to move the drug forward into that disease.
Q: What is the best part of your work?
A: Actually, there are three aspects. The first is that each day is never the same. My work brings together science and business, and increasingly, IT, human elements, economics, and the social sciences. The second aspect thing is that you tend to work with really interesting people. It’s an incredible privilege to work with people who are at the top of their field. The final aspect is the satisfaction of knowing that if you get it right, and if it all works out, it’s going to make a big difference in people’s lives. Take our work in DIPG. We are pursuing that treatment, not because there is a large economic value in it, but because there’s a bigger value beyond economics. The families of those kids don’t really have a lot of hope right now, and we would be very happy if we could bring hope that didn’t exist previously. I think that was part of what I always enjoyed about medicine as well. In that sense, I’ve never ceased to be a doctor. It’s the same thing, just in a different part of the industry.
Q: Anything I haven’t asked?
A: My parting words. I think it is always important to recognize that drug development is difficult and risky. Sometimes, it can even seem like an insurmountable challenge. However, everything is impossible until somebody succeeds. Here in Australia, a relatively common cause of death for younger people is melanoma or skin cancer because we spend significant time outdoors, and we’ve got no real ozone layer to protect us. It Melanoma used to be a death sentence with no effective treatment. I’ve lost people to melanoma that spread and transitioned to metastatic melanoma. Fortunately, that has changed in the last decade. We have seen a number of new treatments approved that have altered the course of that disease. Now, something that has long filled everybody with dread suddenly seems like it may just be beatable one day. Melanoma is still an incredibly challenging disease but it’s not quite as insurmountable as it once was. Our industry did that: the drug development industry brought forward some great new medicines that made a difference. We haven’t completely cured it, don’t get me wrong, but, it’s made an enormous difference. Many people are alive today who wouldn’t be if it weren’t for the drugs that our industry discovered. It’s a great privilege to be a part of an industry that can do that. I very much hope that our company can bring some kind of similar hope to people with brain cancer.
Published on BioSpace