Earlier this week the CIRM ICOC Board awarded $14.5 million to fund three translational stage research projects (TRAN1), whose goal is to support early development activities necessary for advancement to a clinical study or broad end use of a potential therapy. Although all three projects have their distinct area of focus, they all utilize CAR-based cell therapy to treat a certain type of cancer. This approach involves obtaining T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them with a chimeric antigen receptor (CAR). This enables the newly created CAR-engineered cells to identify specific tumor signals and destroy the cancer. In the sections below we will take a deeper look at each one of these recently approved projects.
$2,663,144 was awarded to the University of California, San Francisco (UCSF) to develop specialized CAR-T cells that are able to recognize and destroy tumor cells in glioblastoma, an aggressive type of cancer that occurs in the brain and spinal cord. The specialized CAR-T cells have been created such that they are able to detect two specific signals expressed in glioblastoma. Hideho Okada, M.D., Ph.D. and his team at UCSF will test the therapy in mice with human glioblastoma grafts. They will be looking at preclinical safety and if the CAR-T cell therapy is able to produce a desired or intended result.
$5,949,651 was awarded to the University of California, Los Angeles (UCLA) to develop specialized CAR-engineered cells from human blood stem cells to treat multiple myeloma, a type of blood cancer. Lili Yang, Ph.D. and her team have developed a method using human blood stem cells to create invariant natural killer T (iNKT) cells, a special kind of T cell with unique features that can more effectively attack tumor cells using multiple mechanisms and migrate to and infiltrate tumor sites. After being modified with CAR, the newly created CAR-iNKT cells are able to target a specific signal present in multiple myeloma. The team will test the therapy in mice with human multiple myeloma. They will be looking at preclinical safety and if the CAR-iNKT cells are able to produce a desired or intended result.
Another $5,904,462 was awarded to UCLA to develop specialized CAR-T cells to treat melanoma, a form of skin cancer. Cristina Puig-Saus, Ph.D. and her team will use naïve/memory progenitor T cells (TNM), a subset of T cells enriched with stem cells and memory T cells, an immune cell that remains long after an infection has been eliminated. After modification with CAR, the newly created CAR-TNM cells will target a specific signal present in melanoma. The team will test the therapy in mice with human melanoma. They will be looking at preclinical safety and if the CAR-TNM cells are able to produce a desired or intended result.
Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $14.4 million for two new clinical trials for blood cancer and pediatric brain tumors.
These awards bring the total number of CIRM-funded clinical trials to 70.
$6.0 million was awarded to Immune-Onc Therapeutics to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML), both of which are types of blood cancer. AML affects approximately 20,000 people in the United States each year and has a 5-year survival rate of about 25 percent. Anywhere from 15-30 percent of CMML cases eventually progress into AML.
Paul Woodard, M.D. and his team will treat AML and CMML patients with an antibody therapy called IO-202 that targets leukemic stem cells. The antibody works by blocking a signal named LILRB4 whose expression is connected with decreased rates of survival in AML patients. The goal is to attain complete cancer remissions and prolonged survival.
$8.4 million was also awarded to City of Hope to conduct a clinical trial for children with malignant brain tumors. Brain tumors are the most common solid tumor of childhood, with roughly 5,000 new diagnoses per year in the United States.
Leo D. Wang, M.D., Ph.D. and his team will treat pediatric patients with aggressive brain tumors using chimeric antigen receptor (CAR) T cell therapy. The CAR T therapy involves obtaining a patient’s own T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them so that they are able to identify and destroy the brain tumors. The aim of this approach is to improve patient outcome.
“Funding the most promising therapies for aggressive blood cancer and brain tumors has always aligned with CIRM’s mission,” says Maria T. Millan, M.D., President and CEO of CIRM. “We are excited to fund these trials as the first of many near-term and future stem cell- and regenerative medicine-based approaches that CIRM will be able to support with bond funds under Proposition 14”.
In June of last year we wrote about how Dr. Scott Kitchen and his team at UCLA are engineering blood forming stem cells in order to fight HIV, a potentially deadly virus that attacks the immune system and can worsen into AIDS if left untreated. HIV causes havoc in the body by attacking T cells, a vital part of the body’s immune system that helps fight off infections and diseases.
Dr. Kitchen’s approach uses what is called Chimeric Antigen Receptor (CAR) T gene therapy. This is a type of immune therapy that involves genetically modifying the body’s own blood forming stem cells to create T cells that have the ability to fight HIV. These newly formed immune cells have the potential to not only destroy HIV-infected cells but to create “memory cells” that could provide lifelong protection from HIV infection.
Unfortunately, although the previously designed CAR T gene therapy was still able to create HIV fighting immune cells, the way the CAR T gene therapy was designed still had the potential to allow for HIV infection.
For this new study, the team modified the CAR T gene therapy such that the cells would be resistant to infection and allow for a more efficient and longer-lasting cell response against HIV than before.
While the previous approach allowed for the continuous production of new HIV-fighting T cells that persisted for more than two years, these cells are inactivated until they come across the HIV virus. The improved CAR T gene therapy engineers the body’s immune response to HIV rather than waiting for the virus to induce a response. This is similar in concept to how a vaccine prepares the immune system to respond against a virus. The new approach also creates a significant number of “memory” T cells that are capable of quickly responding to reactivated HIV.
The hope is that these findings can influence the development of T cells that are able carry “immune system” memory with the ability to recognize and kill virus-infected or cancerous cells.
At CIRM we are modest enough to know that we can’t do everything by ourselves. To succeed we need partners. And in UC Davis we have a terrific partner. The work they do in advancing stem cell research is exciting and really promising. But it’s not just the science that makes them so special. It’s also their compassion and commitment to caring for patients.
What follows is an excerpt from an article by Lisa Howard on the work they do at UC Davis. When you read it you’ll see why we are honored to be a part of this research.
Gene therapy research at UC Davis
UC Davis’ commitment to stem cell and gene therapy research dates back more than a decade.
In 2010, with major support from the California Institute for Regenerative Medicine (CIRM), UC Davis launched the UC Davis Institute for Regenerative Cures, which includes research facilities as well as a Good Manufacturing Practice (GMP) facility.
Led by Jan Nolta, a professor of cell biology and human anatomy and the director of the UC Davis Institute for Regenerative Cures, the new center leverages UC Davis’ network of expert researchers, facilities and equipment to establish a center of excellence aimed at developing lifelong cures for diseases.
Nolta began her career at the University of Southern California working with Donald B. Kohn on a cure for bubble baby disease, a condition in which babies are born without an immune system. The blood stem cell gene therapy has cured more than 50 babies to date.
Work at the UC Davis Gene Therapy Center targets disorders that potentially can be treated through gene replacement, editing or augmentation.
“The sectors that make up the core of our center stretch out across campus,” said Nolta. “We work with the MIND Institute a lot. We work with the bioengineering and genetics departments, and with the Cancer Center and the Center for Precision Medicine and Data Sciences.”
A recent UC Davis stem cell study shows a potential breakthrough for healing diabetic foot ulcers with a bioengineered scaffold made up of human mesenchymal stem cells (MSCs). Another recent study revealed that blocking an enzyme linked with inflammation enables stem cells to repair damaged heart tissue. A cell gene therapy study demonstrated restored enzyme activity in Tay-Sachs disease affected cells in humanized mouse models.
“Some promising and exciting research right now at the Gene Therapy Center comes from work with hematopoietic stem cells and with viral vector delivery,” said Nolta.
Hematopoietic stem cells give rise to other blood cells. A multi-institutional Phase I clinical trial using hematopoietic stem cells to treat HIV-lymphoma patients is currently underway at UC Davis.
“We are genetically engineering a patient’s own blood stem cells with genes that block HIV infection,” said Joseph Anderson, an associate professor in the UC Davis Department of Internal Medicine. The clinical trial is a collaboration with Mehrdad Abedi, the lead principal investigator.
“When the patients receive the modified stem cells, any new immune system cell, like T-cell or macrophage, that is derived from one of these stem cells, will contain the HIV-resistant genes and block further infection,” said Anderson.
He explained that an added benefit with the unique therapy is that it contains an additional gene that “tags” the stem cells. “We are able to purify the HIV-resistant cells prior to transplantation, thus enriching for a more protective cell population.
Kyle David Fink
Kyle David Fink, an assistant professor of neurology at UC Davis, is affiliated with the Stem Cell Program and Institute for Regenerative Cures. His lab is focused on leveraging institutional expertise to bring curative therapies to rare, genetically linked neurological disorders.
“We are developing novel therapeutics targeted to the underlying genetic condition for diseases such as CDKL5 deficiency disorder, Angelman, Jordan and Rett syndromes, and Juvenile Huntington’s disease,” said Fink.
The lab is developing therapies to target the underlying genetic condition using DNA-binding domains to modify gene expression in therapeutically relevant ways. They are also creating novel delivery platforms to allow these therapeutics to reach their intended target: the brain.
“The hope is that these highly innovative methods will speed up the progress of bringing therapies to these rare neurodegenerative disease communities,” said Fink.
Jasmine Carter, a graduate research assistant at the UC Davis Stem Cell Program, October 18, 2019. (AJ Cheline/UC Davis)
Developing potential lifetime cures
Among Nolta’s concerns is how expensive gene therapy treatments can be.
“Some of the therapies cost half a million dollars and that’s simply not available to everyone. If you are someone with no insurance or someone on Medicare, which reimburses about 65 percent, it’s harder for you to get these life-saving therapies,” said Nolta.
To help address that for cancer patients at UC Davis, Nolta has set up a team known as the “CAR T Team.”
Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy in which a patient’s own immune cells are reprogrammed to attack a specific protein found in cancer cells.
“We can develop our own homegrown CAR T-cells,” said Nolta. “We can use our own good manufacturing facility to genetically engineer treatments specifically for our UC Davis patients.”
Although safely developing stem cell treatments can be painfully slow for patients and their families hoping for cures, Nolta sees progress every day. She envisions a time when gene therapy treatments are no longer considered experimental and doctors will simply be able to prescribe them to their patients.
“And the beauty of the therapy is that it can work for the lifetime of a patient,” said Nolta.
Bryon Jenkin’s is one of the people we profiled in our recent 18 Month Report. The theme of the report is “Perseverance” and Byron certainly epitomizes that. This is his story.
A former Navy flight officer and accomplished athlete Byron Jenkins learned in June 2013 that he had multiple myeloma, an incurable blood cancer, and that it was eating through his bones. After five years of, chemotherapy, radiation, immunotherapy, and experimental procedures, he found himself bed ridden, exhausted, barely able to move. Byron says: “I was alive, but I wasn’t living.”
As the treatments lost their ability to hold the cancer at bay, Byron’s wife, family and close friends had made preparations for his seemingly inevitable demise.
Then Byron took part in a CIRM-funded CAR-T clinical trial for a treatment developed by Poseida Therapeutics. The team used Byron’s own immune system cells, re-engineered in the lab, to recognize the cancer and to fight back. Within two weeks Byron was feeling so much better he was able to stop taking all of his medications. “I haven’t taken so much as an aspirin since then.”
Two years later he is once again able to enjoy a full, active life with his family; biking, hiking and skiing with his wife and kids. He is back working full-time and only checks in with his oncologist once in a while.
Byron says despite his ordeal he never lost faith, that the love of his family helped give him the strength to continue to fight. “Hope kept me going through this long arduous process. This is the first treatment to give me a continued normal life. CAR-T was the answer to my prayers.”
If that headline seems familiar it should. It came from an article in MIT Technology Review back in 2009. There have been many other headlines since then, all on the same subject, and yet here we are, in 2020, and still no cure for HIV/AIDS. So what’s the problem, what’s holding us back?
First, the virus is incredibly tough and wily. It is constantly mutating so trying to target it is like playing a game of ‘whack a mole’. Secondly not only can the virus evade our immune system, it actually hijacks it and uses it to help spread itself throughout the body. Even new generations of anti-HIV medications, which are effective at controlling the virus, can’t eradicate it. But now researchers are using new tools to try and overcome those obstacles and tame the virus once and for all.
UCLA researchers Scott Kitchen and Irvin Chen have been awarded $13.65 million by the National Institutes of Health (NIH) to see if they can use the patient’s own immune system to fight back against HIV.
Dr. Kitchen and Dr. Chen take the patient’s own blood-forming stem cells and then, in the lab, they genetically engineer them to carry proteins called chimeric antigen receptors or CARs. Once these blood cells are transplanted back into the body, they combine with the patient’s own immune system T cells (CAR T). These T cells now have a newly enhanced ability to target and destroy HIV.
That’s the theory anyway. Lots of research in the lab shows it can work. For example, the UCLA team recently showed that these engineered CAR T cells not only destroyed HIV-infected cells but also lived for more than two years. Now the team at UCLA want to take the lessons learned in the lab and apply them to people.
In a news release Dr. Kitchen says the NIH grant will give them a terrific opportunity to do that: “The overarching goal of our proposed studies is to identify a new gene therapy strategy to safely and effectively modify a patient’s own stem cells to resist HIV infection and simultaneously enhance their ability to recognize and destroy infected cells in the body in hopes of curing HIV infection. It is a huge boost to our efforts at UCLA and elsewhere to find a creative strategy to defeat HIV.”
By the way, CIRM helped get this work off the ground with an early-stage grant. That enabled Dr. Kitchen and his team to get the data they needed to be able to apply to the NIH for this funding. It’s a great example of how we can kick-start projects that no one else is funding. You can read a blog about that early stage research here.
Glioblastoma (GBM) is an aggressive form of cancer that begins in the brain and results in tumors that can be very difficult to treat. This condition has claimed the lives of Beau Biden, former Vice President Joe Biden’s son, and John McCain, former Senator of Arizona. However, a new approach to combat this condition is being developed at City of Hope and has just received approval from the FDA to conduct clinical trials. The innovative approach involves using a combination of chimeric antigen receptor (CAR)-T cell therapy and specific components of scorpion venom!
Before we dive into how the scorpion venom is being used, what exactly is CAR-T cell therapy?
This approach consists of using T cells, which are an immune system cell that can destroy foreign or abnormal cells, and modifying them with a protein called a chimeric antigen receptor (CAR). These newly designed CAR-T cells are able to identify and destroy cancer cells by detecting a specific protein on these cells. What makes CAR-T cell even more promising is that the specific protein detected can be set to virtually anything.
This is where the scorpion venom comes into play. One of the components of this venom is called chlorotoxin (CLTX), which has the ability to specifically bind to brain tumor cells.
For this study, Dr. Christine Brown, Dr. Michael Barish, and a team of researchers at City of Hope designed CAR-T cells using chlorotoxin in order to specifically detect and destory brain tumor cells. Now referred to as CLTX-CAR-T cells, they found that these newly engineered cells were highly effective at selectively killing brain tumor cells in animal models. What’s more remarkable is that the CLTX-CAR-T cells ignored non-tumor cells in the brain and other organs.
In a press release, Dr. Barish describes the CLTX-CAR-T cell approach in more detail.
“Much like a scorpion uses toxin components of its venom to target and kill its prey, we’re using chlorotoxin to direct the T cells to target the tumor cells with the added advantage that the CLTX-CAR T cells are mobile and actively surveilling the brain looking for appropriate target. We are not actually injecting a toxin, but exploiting CLTX’s binding properties in the design of the CAR. The idea was to develop a CAR that would target T cells to a wider variety of GBM tumor cells than the other antibody-based CARs.”
In the same press release, Dr. Brown talks about the promise of this newly developed therapy.
“Our chlorotoxin-incorporating CAR expands the populations of solid tumors potentially targeted by CAR T cell therapy, which is particularly needed for patients with cancers that are difficult to treat such as glioblastoma. This is a completely new targeting strategy for CAR T therapy with CARs incorporating a recognition structure different from other CARs.”