UC Davis Health researchers aim to use CAR T cells for HIV cure

Dr. Abedi (right) in the lab at UC Davis Health. He and his team of researchers have launched a study looking to identify a potential cure for HIV. Photo Courtesy of UC Davis Health.

Worldwide, almost 38 million people are living with HIV—the virus that can lead to AIDS— and it’s estimated that 75% of them receive antiviral treatment to keep the virus in check. In California, 150,000 people live with HIV and 68% of these individuals are virally suppressed due to treatment.  

To fight this virus, UC Davis Health researchers—with funding from a CIRM grant—have launched a study looking to identify a potential cure for HIV. Using immunotherapy, researchers will take a patient’s own white blood cells, called T-cells, and modify them so that they can identify and target HIV cells to control the virus without medication. 

Targeting HIV with CAR T cells

“For this study we will educate the cells by inserting a gene to target cells that have been infected by the HIV virus,” explained Mehrdad Abedi, professor of internal medicine, hematology and oncology and the principal investigator of the study. “The idea is these modified cells will attach to the HIV-infected cells and destroy the cells that are infected while also stopping the infected cells’ ability to replicate.” 

Modified T-cells, known as CAR T cells, are an FDA-approved treatment for different forms of cancer including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma. With cancer, the immune system often fails to deploy T-cells right away or at all. When it does, the attack is ineffective. CAR T-cell immunotherapy changes these collected T-cells to produce chimeric antigen receptors (or CARs) that adhere to tumors to destroy them. 

Study seeking HIV patients

For the study, UC Davis Health researchers are working to identify and recruit HIV-positive patients between the ages of 18 and 65 who have had an undetectable HIV viral load for the 12 months and have been on continuous antiretroviral therapy for at least 12 months.  

Patients also need to be willing to pause their antiretroviral therapy as part of the study. 

“While it is exciting, the study will require a lot of dedication from the patient because of the time commitment involved and the necessary steps required,” said Paolo Troia-Cancio, a clinical professor of medicine with the infectious disease division with over 20 years of experience treating HIV and co-investigator on the CAR T cell study.   

The search for an HIV cure 

Three patients have been cured of HIV using bone marrow transplants, including a woman in New York who received a cord blood stem cell transplant. She received a bone marrow transplant using umbilical cord blood donor cells that bore a mutation that makes them resistant to HIV infection to treat her leukemia. 

There have also been two previous cases involving an HIV cure following allogeneic bone marrow transplants. Both patients had leukemia and received bone marrow transplants from donors who carried the same mutation that blocks HIV infection.  

“While these stories provide inspiration and hope to finding a cure for HIV, a bone marrow transplant is not a realistic option for most patients,” said Abedi. “Such transplants are highly invasive and risky, so they are generally offered only to people with cancer who have exhausted all other options.” 

Abedi and his fellow researchers see this study as a potential road map to finding a cure for HIV.  

The California Institute for Regenerative Medicine (CIRM) has funded earlier work by Dr. Abedi and his team in trying to develop a therapy to help people with HIV who also have lymphoma.  

To read the source article about this CIRM-funded study, click here

Researchers discover promising approach against treatment-resistant cancer

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

Photo: Albert Einstein College of Medicine 

Researchers at Albert Einstein College of Medicine have devised a promising strategy for overcoming a key cause of cancer deaths: the ability of cancer cells to thrive in the face of chemotherapy drugs designed to destroy them.  

There are cells, called cancer stem cells, that have the ability to evade chemotherapy and lie dormant for a while. But later they can become active again, generate more cancer cells, and cause relapses.  

Published in the March 7 issue of Nature Communications, investigators used a two-drug combination to achieve chemotherapy’s goal: to make cancer cells self-destruct via the biological process known as apoptosis—also known as programmed cell death. 

The treatment worked against human cancer cell lines that resisted apoptosis despite exposure to different types of chemotherapy, and against apoptosis-resistant human tumors implanted in mice. 

“We need new, broadly active therapies that can attack a range of cancers while causing fewer side effects than current treatments, and we hope our new therapeutic strategy will prove to be a viable option,” said Evripidis Gavathiotis, PhD, professor of biochemistry and of medicine at Einstein and corresponding author on the paper. 

How Apoptosis Works 

The body relies on apoptosis for getting rid of unwanted cells, including damaged cells that need to be removed so they don’t develop into cancer cells. Both chemotherapy and radiation rely on damaging cancer cells so they undergo apoptosis, but that doesn’t always happen. 

Every cell in the body contains some two dozen apoptotic proteins that promotes its own destruction. Some proteins stimulate apoptosis (pro-apoptotic proteins), while others block the process (anti-apoptotic proteins).  

BAX—The Executioner Protein

The new drug combination discovered by researchers at Einstein kills apoptosis-resistant cancer cells by boosting the active form of one pro-apoptotic protein in particular: BAX, dubbed the “executioner protein.” They then combined that with Navitoclax, an investigational  cancer drug that blocked the activity of proteins that inhibit the effectiveness of BAX. 

When the Einstein team tested the drug duo against 46 human blood and solid tumor cell lines, it packed a one-two punch, boosting active BAX to toxic levels in cancer cells, and Navitoclax acting as BAX’s bodyguard by preventing other proteins from neutralizing BAX. 

Limiting Side Effects 

The two orally-administered drugs were then tested in mice implanted with tumor cells from a colorectal-cancer cell line that had resisted one version of BAX and Navitoclax as individual drugs but had succumbed to their combined use. The in vivo experiment produced similar results.  

Individually, each drug had limited effectiveness in reducing tumor growth, while combining them significantly suppressed tumor growth, indicating that the two drugs act synergistically to defeat apoptosis-resistant tumors. 

“Equally important, mice receiving the two-drug combination tolerated it remarkably well,” noted Dr. Gavathiotis. “Moreover, analysis of the treated mice showed that healthy cells were not affected by the two-drug combination—likely making it safer than standard chemotherapies, which are toxic to all dividing cells, both cancerous and normal.” 

Read the source article here.

CIRM CNS Consortium Workshop – Held Feb. 24 & 25, 2022

Note: Post edited to include post-event workshop videos. Watch both workshop videos here and here.

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

Shared Stem Cell Laboratory at UCLA

Advance World Class Science, Deliver Real World Solutions, Provide Opportunity for All. 

These comprise the themes of our bold 5-year Strategic Plan. Since its launch less than two months ago, we have hit the ground running. Under the second and third strategic themes, we have already received ICOC approval for 2 concepts: Alpha Clinics Network Expansion and COMPASS educational program. We are now working on the execution of our first theme.  

As indicated in our Strategic Plan, we strongly believe advancing world class science relies on collaborative research that leverages collective scientific knowledge. To that end, we have organized the virtual CIRM CNS Consortium Workshop (click for the agenda and see registration details below) to help us gather feedback from a panel of experts about the best approach for promoting a culture of collaboration.

The vision for this workshop was informed by multiple layers of stakeholder discussions and input that started even prior to the passage of Proposition 14. A quick walk down memory lane reminds us of CIRM’s early and deliberate effort to identify areas of opportunity for promoting a paradigm shift with a “team science” approach, especially in the context of complex diseases such as those affecting the CNS: 

  • In 2019, we organized Brainstorming Neurodegeneration, a workshop where broad stakeholder input was received about the benefits and bottlenecks of developing a consortium approach where genomics and big data, novel stem cell models, and patient data could be collectively leveraged to advance the field of neurodegenerative research in a collaborative manner.  
  • In 2020, just before the passage of Prop 14 and based on input from the 2019 workshop, we already had our eyes on target: the future of collaborative research is in sharable data, and sharing petabytes or more of data requires a collaborative data infrastructure. To better understand the status and bottlenecks of knowledge platforms that could leverage data sharing, we brought together a panel of experts at our 2020 Grantee Meeting. We were encouraged to learn that our laser-focused approach for promoting knowledge sharing was right on target and the panelists suggested that CIRM has a great opportunity to promote a paradigm shift in this area.   
  • In early 2021, immediately after the passage of Prop 14 and building upon our previous conversations, we formed a Strategic Scientific Advisory Panel comprising a distinguished group of national and international scientists in the stem cell field. Once again, we were advised to expand sharable resources (especially in the context of stem cell modeling), bring more attention to complex diseases such as neurodegenerative and neuropsychiatric disorders, and facilitate knowledge sharing.  
  • In mid 2021, as we were forming our Strategic Plan based on the above input, we pressure-tested our paradigm-shifting vision in a Town Hall and further gathered feedback from California stakeholders about their needs. Again, all arrows pointed to shared resources and data as critical elements for accelerating research.  
CIRM Town Hall workshop hosted in 2021
  • Finally, in late 2021, just before the launch of our Strategic Plan, we organized a Data Biosphere Advisory Committee to advise us on ways to facilitate collaborative knowledge sharing. Here, we explored various models for leveraging and/or generating a data infrastructure in which CIRM-funded data could be managed and shared. The main outcome of this meeting was a recommendation to organize a workshop to test the feasibility and approach for generation of a CIRM knowledge platform. The Committee concluded that CIRM is uniquely positioned to contribute a wealth of data to the broader scientific community. A knowledge platform would provide an avenue for data sharing and collaboration with other groups that are dedicated to accelerating progress in the development of therapies, especially for CNS disorders.  

We were walking on solid ground! In December of 2021, paralleling the input we had received from experts and stakeholders, we launched our 5-year Strategic Plan with the goal of advancing world class science by promoting a culture of collaboration. 

To deliver on this goal, CIRM’s approach is to build the infrastructure (and we don’t mean bricks and mortar) that organizes and democratizes data through:  

  1. A network of shared resources labs that facilitate validation and standardization to support California regenerative medicine researchers  
  1. A data infrastructure where CIRM-funded data can be shared and external datasets leveraged to maximize real-world impact  
  1. We have held a virtual CNS Consortium Workshop on February 24th and 25th where we explored the development of these two resources through the deployment of a consortium and starting in the CNS space as a use case. While the discussions at the workshop centered on the CNS, the shared resources labs will be implemented across cell types and organs. The Data Infrastructure is intended to be a global resource for data sharing and fostering a culture of open science for all CIRM grantees—and the world. The complete workshop agenda can be found here.  

    Watch video recordings of Day 1 and Day 2 of the CNS workshop.

Stem cell discovery could help shorten cancer treatment recovery 

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

A researcher prepares to study blood cells under a microscope. Photo by Getty.

A recent discovery by stem cell scientists at Cedars-Sinai may help make cancer treatment more efficient and shorten the time it takes for people to recover from radiation and chemotherapy.  

Published in the journal Nature Communications, the study by Dr. John Chute and his team (and co-funded by CIRM) revealed a mechanism through which the blood vessels in the bone marrow respond to injury, such as from chemotherapy or radiation. 

Each year, about 650,000 cancer patients receive chemotherapy in an outpatient oncology clinic in the United States.  

When people receive radiation or chemotherapy as part of their cancer treatment, their blood counts plummet. It typically takes several weeks for these counts to return to normal levels. During this period patients are at risk for developing infections that may lead to hospitalization, disruptions in chemotherapy schedules, and even death. 

Chute and his colleagues found that when mice receive radiation treatment, the cells that line the inner walls of the blood vessels in the bone marrow produce a protein called semaphorin 3A. This protein tells another protein, called neuropilin 1, to kill damaged blood vessels in the bone marrow. 

When the investigators blocked the ability of these blood vessel cells to produce neuropilin 1 or semaphorin 3A, or injected an antibody that blocks semaphorin 3A communication with neuropilin 1, the veins and arteries in the bone marrow regenerated faster following irradiation. In addition, blood counts increased dramatically after one week. 

“We’ve discovered a mechanism that appears to control how blood vessels regenerate following injury,” said Chute, senior author of the paper. “Inhibiting this mechanism causes rapid recovery of the blood vessels and blood cells in bone marrow following chemotherapy or irradiation.”  

In principle, Chute said, targeting this mechanism could allow patients to recover following chemotherapy in one to two weeks, instead of three or four weeks as currently experienced. 

Christina M. Termini, a post-doctoral scientist at the David Geffen School of Medicine at UCLA, was the first author of this study. Read the source press release here.  

Old therapies inspire new hope for treatment of pediatric brain tumors

THIS BLOG IS ALSO AVAILABLE AS AN AUDIO CAST

Image courtesy St. Jude Children’s Research Hospital

A recent study led by John Hopkins Medicine has found that combining two ‘old therapies’ can offer a surprising new purpose – fighting Medulloblastoma, the most common malignant brain tumor in children. The fast-growing cancerous tumor originates in the brain or spinal cord and has traditionally been treated with surgery to remove the tumor followed by radiation and chemotherapy. 

The prospective therapy which comprises of copper ions and Disulfiram (DSF-Cu++), paves the way toward a successful treatment that can be used alone or in conjunction with traditional therapy. “Disulfiram, [is] a medication that’s been used for nearly 70 years to treat chronic alcoholism,” explains Betty Tyler, the study’s senior author and associate professor of neurosurgery at Johns Hopkins. “It has great promise being ‘repurposed’ as an anticancer agent, especially when it is complexed with metal ions such as copper.”

The researchers tested the anticancer activity of DSF-Cu++ and, in their attempts to define what it targeted at the molecular level to achieve these effects, were able to highlight four key findings.

First, the team of researchers found that DSF-Cu++ blocks two biological pathways in medulloblastomas that the cancer cells need in order to remove proteins threatening their survival. With these pathways blocked, these proteins accumulate in the tumor and cause the malignant cells to die, leaving them to eventually be removed by the body’s own immune system. 

Second, the researchers discovered that just a few hours of exposure to DSF-Cu++ not only kills medulloblastoma cells but can also effectively reduce the cancer stem cells responsible for their creation. 

The third finding in the study revealed that DSF-CU++ keeps cancer cells from recovering. By impairing the ability of medulloblastoma cells to repair the damage done to their DNA, DSF-CU++ enhances the cell killing power of the treatment.

Lastly, the promising combo of DSF-CU++ demonstrated significant increases in prolonging survival days of mice whose brains were implanted with two subtypes of medulloblastoma. 

Lung cancer, Sherlock Holmes and piano

THIS BLOG IS ALSO AVAILABLE AS AN AUDIOCAST ON SPOTIFY

Image of lung cancer

When we think of lung cancer we typically tend to think it’s the end result of years of smoking cigarettes. But, according to the Centers for Disease Control and Prevention, between 10 and 20 percent of cases of lung cancer (20,000 to 40,000 cases a year) happen to non-smokers, people who have either never smoked or smoked fewer than 100 cigarettes in their life. Now researchers have found that there are different genetic types of cancer for smokers and non-smokers, and that might mean the need for different kinds of treatment.

A team at the National Cancer Institute did whole genome sequencing on tumors from 232 never-smokers who had lung cancer. In an interview with STATnews, researcher Maria Teresa Landi said they called their research the Sherlock-Lung study, after the famous fictional pipe-smoking detective Sherlock Holmes. “We used a detective approach. By looking at the genome of the tumor, we use the changes in the tumors as a footprint to follow to infer the causes of the disease.”

They also got quite creative in naming the three different genetic subtypes they found. Instead of giving them the usual dry scientific names, they called them piano, mezzo-forte and forte; musical terms for soft, medium and loud.

Half of the tumors in the non-smokers were in the piano group. These were slow growing with few mutations. The median latency period for these (the time between being exposed to something and being diagnosed) was nine years. The mezzo-forte group made up about one third of the cases. Their cancers were more aggressive with a latency of around 14 weeks. The forte group were the most aggressive, and the ones that most closely resembled smokers’ cancer, with a latency period of just one month.

So, what is the role of stem cells in this research? Well, in the study, published in the journal Nature Genetics the team found that the piano subtype seemed to be connected to genes that help regulate stem cells. That complicates things because it means that the standard treatments for lung cancer that work for the mezzo-forte and forte varieties, won’t work for the piano subtype.

“If this is true, it changes a lot of things in the way we should think of tumorigenesis,” Dr. Landi said.

With that in mind, and because early-detection can often be crucial in treating cancer, what can non-smokers do to find out if they are at risk of developing lung cancer? Well, right now there are no easy answers. For example, the U.S. Preventive Services Task Force does not recommend screening for people who have never smoked because regular CT scans could actually increase an otherwise healthy individual’s risk of developing cancer.

New technique maps out diversity and location of cells in tissue or tumor

Image Description: Alex Marson is part of a team of researchers who developed a new technique to map the specialized diversity and spatial location of individual cells within a tissue or tumor. Photo Credit: Anastasiia Sapon

All the cells in your body work together and each can have a different role. Their individual function not only depends on cell type, but can also depend on their specific location and surroundings.

A CIRM supported and collaborative study at the Gladstone Institutes, UC San Francisco (UCSF), and UC Berkeley has developed a more efficient method than ever before to simultaneously map the specialized diversity and spatial location of individual cells within a tissue or a tumor.

The technique is named XYZeq and involves segmenting a tissue into microscopic regions. Within each of these microscopic grids, each cell’s genetic information is analyzed in order to better understand how each particular cell functions relative to its spacial location.

For this study, the team obtained tissue from mice with liver and spleen tumors. A slice of tissue was then placed on a slide that divides the tissue into hundreds of “microwells” the size of a grain of salt. Each cell in the tissue gets tagged with a unique “molecular barcode” that represents the microwell it’s contained in, much like a zip code. The cells are then mixed up and assigned a second barcode to ensure that each cell within a given square can be individually identified, similar to a street address within a zip code. Finally, the genetic information in the form of RNA from each cell is analyzed. Once the results are obtained, both barcodes tell the researchers exactly where in the tissue it came from.

The team found that some cell types located near the liver tumor were not evenly spaced out. They also found immune cells and specific types of stem cells clustered in certain regions of the tumor. Additionally, certain stem cells had different levels of some RNA molecules depending on how far they resided from the tumor.

The researchers aren’t entirely sure what this pattern means, but they believe that it’s possible that signals generated by or near the tumor affect what nearby cells do.

In a press release, Alex Marson, M.D., Ph.D., a senior author of the study, elaborates on what the XYZeq technology could mean for disease modeling.

“I think we’re actually taking a step toward this being the way tissues are analyzed to diagnose, characterize, or study disease; this is the pathology of the future.”

The full results of the study were published in Science Advances.

CIRM Board Approves Clinical Trials for Blood Cancer and Pediatric Brain Tumors

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”.

Saying thanks and farewell to a friend

Tom Howing

In this job you get to meet a lot of remarkable people, none more so than the patients who volunteer to take part in what are giant experiments. They are courageous pioneers, willing to be among the first people to ever try a new therapy, knowing that it may not help them and, potentially, might even harm them.

Tom Howing was one such person. I got to know Tom when we were putting together our 2017 Annual Report. Back in 2015 Tom was diagnosed with Stage 4 cancer that had spread throughout his body. He underwent surgery and chemotherapy. That worked for a while, but then the cancer returned. So, Tom had more surgery and chemotherapy. Again, it worked for a while but when the cancer returned again Tom was running out of options.

That’s when he learned about a clinical trial with a company called Forty Seven Inc. that was testing a new anti-cancer therapy that CIRM was supporting. Tom says he didn’t hesitate.

“When I was diagnosed with cancer I knew I had battle ahead of me. After the cancer came back again they recommended I try this CD47 clinical trial. I said absolutely, let’s give it a spin. I guess one is always a bit concerned whenever you put the adjective “experimental” in front of anything. But I’ve always been a very optimistic and positive person and have great trust and faith in my caregivers.”

Optimistic and positive are great ways to describe Tom. Happily, his optimism was rewarded. The therapy worked.

“Scans and blood tests came back showing that the cancer appears to be held in check. My energy level is fantastic. The treatment that I had is so much less aggressive than chemo, my quality of life is just outstanding.”

But after a year or so Tom had to drop out of the trial. He tried other therapies and they kept the cancer at bay. For a while. But it kept coming back. And eventually Tom ran out of options. And last week, he ran out of time.

Tom was a truly fine man. He was kind, caring, funny, gracious and always grateful for what he had. He talked often about his family and how the stem cell therapy helped him spend not just more time with them, but quality time.

He knew when he signed up for the therapy that there were no guarantees, but he wanted to try, saying that even if it didn’t help him that the researchers might learn something to help others down the line.

“The most important thing I would say is, I want people to know there is always hope and to stay positive.”

Tom ultimately lost his battle with cancer. But he never lost his spirit, his delight in his family and his desire to keep going as long as he could. In typical Tom fashion he preferred to put his concerns aside and cheer others along.

“To all those people who are putting in all the hours at the bench and microscope, it’s important for them to know that they are making a huge impact on the lives of real people and they should celebrate it and revel in it and take great pride in it.”

We consider ourselves fortunate to have known Tom and to have been with him on part of his journey. He touched our lives, as he touched the lives of so many others. Our thoughts and wishes go out to his family and friends. He will be remembered, because we never forget our friends.

A few years ago Tom came and talked to the CIRM Board. Here is the video of that event.

A word from our Chair, several in fact

In 2005, the New Oxford American Dictionary named “podcast” its word of the year. At the time a podcast was something many had heard of but not that many actually tuned in to. My how times have changed. Now there are some two million podcasts to chose from, at least according to the New York Times, and who am I to question them.

Yesterday, in the same New York Times, TV writer Margaret Lyons, wrote about how the pandemic helped turn her from TV to podcasts: “Much in the way I grew to prefer an old-fashioned phone call to a video chat, podcasts, not television, became my go-to medium in quarantine. With their shorter lead times and intimate production values, they felt more immediate and more relevant than ever before.”

I mention this because an old colleague of ours at CIRM, Neil Littman, has just launched his own podcast and the first guest on it was Jonathan Thomas, Chair of the CIRM Board. Their conversation ranged from CIRM’s past to the future of the regenerative field as a whole, with a few interesting diversions along the way. It’s fun listening. And as Margaret Lyons said it might be more immediate and more relevant than ever before.