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.
Today the governing Board of the California Institute for Regenerative Medicine (CIRM) awarded $750,000 to Dr. Xiaokui Zhang at Celularity to conduct a clinical trial for the treatment of COVID-19. This brings the total number of CIRM clinical trials to 64, including three targeting the coronavirus.
This trial will use blood stem cells obtained from the placenta to generate natural killer (NK) cells, a type of white blood cell that is a vital part of the immune system, and administer them to patients with COVID-19. NK cells play an important role in defense against cancer and in fighting off viral infections. The goal is to administer these cells to locate the active sites of COVID-19 infection and destroy the virus-infected cells. These NK cells have been used in two other clinical trials for acute myeloid leukemia and multiple myeloma.
The Board also approved two additional awards for Discovery Stage Research (DISC2), which promote promising new technologies that could be translated to enable broad use and improve patient care.
One award for $100,000 was given to Dr. Albert Wong at Stanford. Dr. Wong has recently received an award from CIRM to develop a vaccine that produces a CD8+ T cell response to boost the body’s immune response to remove COVID-19 infected cells. The current award will enable him to expand on the initial approach to increase its potential to impact the Latinx and African American populations, two ethnicities that are disproportionately impacted by the virus in California.
The other award was for $249,996 and was given to Dr. Preet Chaudhary at the University of Southern California. Dr. Chaudary will use induced pluripotent stem cells (iPSCs) to generate natural killer cells (NK). These NK cells will express a chimeric antigen receptor (CAR), a synthetic receptor that will directly target the immune cells to kill cells infected with the virus. The ultimate goal is for these iPSC-NK-CAR cells to be used as a treatment for COVID-19.
“These programs address the role of the body’s immune T and NK cells in combatting viral infection and CIRM is fortunate enough to be able to assist these investigators in applying experience and knowledge gained elsewhere to find targeted treatments for COVID-19” says Dr. Maria T. Millan, the President & CEO of CIRM. “This type of critical thinking reflects the resourcefulness of researchers when evaluating their scientific tool kits. Projects like these align with CIRM’s track record of supporting research at different stages and for different diseases than the original target.”
The CIRM Board voted to endorse a new initiative to refund the agency and provide it with $5.5 billion to continue its work. The ‘California Stem Cell Research, Treatments and Cures Initiative of 2020 will appear on the November ballot.
The Board also approved a resolution honoring Ken Burtis, PhD., for his long service on the Board. Dr. Burtis was honored for his almost four decades of service at UC Davis as a student, professor and administrator and for his 11 years on the CIRM Board as both a member and alternate member. In the resolution marking his retirement the Board praised him, saying “his experience, commitment, knowledge, and leadership, contributed greatly to the momentum of discovery and the future therapies which will be the ultimate outcome of the dedicated work of the researchers receiving CIRM funding.”
Jonathan Thomas, the Chair of the Board, said “Ken has been invaluable and I’ve always found him to have tremendous insight. He has served as a great source of advice and inspiration to me and to the ICOC in dealing with all the topics we have had to face.”
Lauren Miller Rogen thanked Dr. Burtis, saying “I sat next to you at my first meeting and was feeling so extraordinarily overwhelmed and you went out of your way to explain all these big science words to me. You were always a source of help and support, and you explained things to me in a way that I always appreciated with my normal brain.”
Dr. Burtis said it has been a real honor and privilege to be on the Board. “I’ve been amazed and astounded at the passion and dedication that the Board and CIRM staff have brought to this work. Every meeting over the years there has been a moment of drama and then resolution and this Board always manages to reach agreement and serve the people of California.”
The COVID-19 virus targets many different parts of the body, often with deadly or life-threatening consequences. This past Friday the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investments in three early-stage research programs taking different approaches to battling the virus.
Dr. Jianhua Yu at the Beckman Research Institute of City of Hope was awarded $150,000 to use stem cells from umbilical cord blood to attack the virus. Dr. Yu and his team have many years of experience in taking cord blood cells and turning them into what are called chimeric antigen receptor (CAR) natural killer (NK) cells. The goal is to deploy these CAR NK cells to specifically target cells infected with COVID-19. This leverages the body of work at the City of Hope to develop this technology for cancer.
Dr. Helen Blau of Stanford University was awarded $149,996 to target recovery of muscle stem cells of the diaphragm in COVID-19 patients who have an extended period on a ventilator.
Patients with severe coronavirus often suffer respiratory failure and end up on mechanical ventilation that takes over the work of breathing. Over time, the diaphragm, the main muscle responsible for inhaling and exhaling, weakens and atrophies. There is no treatment for this kind of localized muscle wasting and it is anticipated that some of these patients will take months, if not years, to fully recover. Dr. Blau’s team proposes to develop a therapy with Prostaglandin E2 and Bupivacaine based on data generated by Dr. Blau’s group that these drugs, already approved by the FDA for other indications, have the potential to stimulate muscle stem cell recovery.
Dr. Albert Wong, also from Stanford University, was awarded $149,999 to develop vaccine candidates against COVID-19.
Most vaccine candidates are focused on getting the body to produce an antibody response to block the virus. However, Dr. Wong thinks that to be truly effective, a vaccine also needs to produce a CD8+ T cell response to augment an effective immune response to remove the COVID-19 infected cells that are hijacked by the virus to spread and cause illness. This team will use the experience it gained using CIRM funds to vaccine against glioblastoma, a deadly brain cancer, to advance a similar approach to produce an effective cellular immune response to combat COVID-19.
“CIRM is committed to supporting novel, multi-pronged approaches to battle this COVID-19 crisis that leverage solid science and knowledge gained in other areas.” says Dr. Maria T. Millan, the President & CEO of CIRM. “These three projects highlight three very different approaches to combatting the acute devastating health manifestations of COVID-19 as well as the debilitating sequelae that impact the ability to recover from the acute illness. Through this COVID funding opportunity, CIRM is enabling researchers to re-direct work they have already done, often with CIRM support, to quickly develop new approaches to COVID-19.”
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.”