When Lili Yang was studying for her PhD she approached her mentor, the Nobel Laureate Dr. David Baltimore, and told him she was thinking about writing her thesis on a combination of gene therapy, immunotherapy and stem cell therapy. She says he looked at her and told her that all three of those approaches had a bad reputation because of so many past failures. He asked her, “Are you sure?” She was.
Fast forward 20 years and Dr. Yang and her team at UCLA have developed stem cell-engineered invariant Natural Killer T (iNKT) cells, a kind of specialized immune system cell, that has the ability to attack and kill a broad range of cancerous cells, while leaving the body’s healthy tissues unharmed.
Thanks to several CIRM grants, Dr. Yang has developed a platform that can use healthy donor blood stem cells to produce clinical scalable “off-the-shelf” iNKT cells. That has led to the creation of Appia Bio, a start-up company, and talks with the FDA about testing a series of iNKT cell products in clinical trials.
Besides developing cell products targeting the more established blood cancer disease indications, Dr. Yang is most excited about using the same platform to generate off-the-shelf iNKT cell products that could target solid tumor cancers that comprise over 90% of the total cancer cases, such as breast, ovarian, prostate, lung, liver, and colon cancers.
“I have this dream that cell therapy can become off-the-shelf, and how this would really help all cancer patients in need. The current cancer cell therapy requires treating patients one-by-one, resulting in a steep price that is hard to afford ($300,000-$500,000 per patient per treatment) and a complex therapy delivery logistics that is challenging to fulfill (coordination of hospitalization, blood collection, cell manufacturing and infusion for each patient). Not everyone lives near a hospital capable of handling such a personalized therapy or can afford such a steep price. If we can make this therapy with centralized manufacturing, pre-quality controlled and ready for wide use then we don’t need to worry about the gender or age or location of the patient. For off-the-shelf therapy, price is also expected to drop down significantly- this will eventually be ready for everyone everywhere.”
While stem cell and gene therapy research has advanced dramatically in recent years, there are still many unknowns and many questions remaining about how best to use these approaches in developing therapies. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) today approved investing almost $25 million in 19 projects in early stage or Discovery research.
The awards are from CIRM’s DISC2 Quest program, which supports the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.
“Every therapy that helps save lives or change lives begins with a researcher asking a simple question, “What if?”, says Dr. Maria T. Millan, the President and CEO of CIRM. “Our Quest awards reflect the need to keep supporting early stage research, to gain a deeper understanding of stem cells work and how we can best tap into that potential to advance the field.”
Dr. Judy Shizuru at Stanford University was awarded $1.34 million to develop a safer, less-toxic form of bone marrow or hematopoietic stem cell transplant (HCT). HCT is the only proven cure for many forms of blood disorders that affect people of all ages, sexes, and races worldwide. However, current methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
Dr. Shizuru proposes developing an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells. This would make stem cell transplant safer and more effective for the treatment of many life-threatening blood disorders, and more accessible for people in rural or remote parts of the country.
Dr. Lili Yang at UCLA was awarded $1.4 million to develop an off-the-shelf cell therapy for ovarian cancer, which causes more deaths than any other cancer of the female reproductive system.
Dr. Yang is using immune system cells, called invariant natural killer T cells (iNKT) to attack cancer cells. However, these iNKT cells are only found in small numbers in the blood so current approaches involve taking those cells from the patient and, in the lab, modifying them to increase their numbers and strength before transplanting them back into the patient. This is both time consuming and expensive, and the patient’s own iNKT cells may have been damaged by the cancer, reducing the likelihood of success.
In this new study Dr. Yang will use healthy donor cord blood cells and, through genetic engineering, turn them into the specific form of iNKT cell therapy targeting ovarian cancer. This DISC2 award will support the development of these cells and do the necessary testing and studies to advance it to the translational stage.
Timothy Hoey and Tenaya Therapeutics Inc. have been awarded $1.2 million to test a gene therapy approach to replace heart cells damaged by a heart attack.
Heart disease is the leading cause of death in the U.S. with the highest incidence among African Americans. It’s caused by damage or death of functional heart muscle cells, usually due to heart attack. Because these heart muscle cells are unable to regenerate the damage is permanent. Dr. Hoey’s team is developing a gene therapy that can be injected into patients and turn their cardiac fibroblasts, cells that can contribute to scar tissue, into functioning heart muscle cells, replacing those damaged by the heart attack.
Immunotherapy is a type of cancer treatment that uses a person’s own immune system to fight cancer. It comes in a variety of forms including targeted antibodies, cancer vaccines, and adoptive cell therapies. While immunotherapies have revolutionized the treatment of aggressive cancers in recent decades, they must be created on a patient-specific basis and as a result can be time consuming to manufacture/process and incredibly costly to patients already bearing the incalculable human cost of suffering from the cruelest disease.
Fortunately, the rapid progress that has led to the present era of cancer immunotherapy is expected to continue as scientists look for ways to improve efficacy and reduce cost. Just this week, a CIRM-funded study published in Cell Reports Medicine revealed a critical step forward in the development of an “off-the-shelf” cancer immunotherapy by researchers at UCLA. “We want cell therapies that can be mass-produced, frozen and shipped to hospitals around the world,” explains Lili Yang, the study’s senior author.
In order to fulfil this ambitious goal, Yang and her colleagues developed a new method for producing large numbers of a specialized T cell known as invariant natural killer T (iNKT) cells. iNKT cells are rare but powerful immune cells that don’t carry the risk of graft-versus-host disease, which occurs when transplanted cells attack a recipient’s body, making them better suited to treat a wide range of patients with various cancers.
Using stem cells from donor cord-blood and peripheral blood samples, the team of researchers discovered that one cord blood donation could produce up to 5,000 doses of the therapy and one peripheral blood donation could produce up to 300,000 doses. The high yield of the resulting cells, called hematopoietic stem cell-engineered iNKT (HSC–iNKT) cells,could dramatically reduce the cost of producing immune cell products in the future.
In order to test the efficacy of the HSC–iNKT cells, researchers conducted two very important tests. First, they compared its cancer fighting abilities to another set of immune cells called natural killer cells. The results were promising. The HSC–iNKT cells were significantly better at killing several types of tumor cells such as leukemia, melanoma, and lung cancer. Then, the HSC–iNKT cells were frozen and thawed, just as they would be if they were to one day become an off-the-shelf cell therapy. Researchers were once again delighted when they discovered that the HSC–iNKT cells sustained their tumor-killing efficacy.
Next, Yang and her team added a chimeric antigen receptor (CAR) to the HSC–iNKT cells. CAR is a specialized molecule that can enable immune cells to recognize and kill a specific type of cancer. When tested in the lab, researchers found that CAR-equipped HSC–iNKT cells eliminated the specific cancerous tumors they were programmed to destroy.
This study was made possible in part by three grants from CIRM.
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.
Within all of our bodies there is a special type of “super” immune cell that holds enormous potential. Unlike regular immune cells that can only attack one cancer at a time, these “super” immune cells have the ability to target many types of cancers at once. These specialized cells are known as invariant natural killer T cells or iNKT cells for short. Unfortunately, there are relatively few of these cells normally present in the body.
However, in a CIRM-funded study, Dr. Lily Yang and her team of researchers at UCLA have found a way to produce iNKT cells from human blood stem cells. They were then able to test these iNKT cells on mice with both human bone marrow and human cancers. These mice either had multiple melanoma, a type of blood cancer, or melanoma, a solid tumor cancer. The researchers then studied what happened to mice’s immune system, cancers, and engineered iNKT cells after they had integrated into the bone marrow.
The results were remarkable. The team found that the blood stem cells now differentiated normally into iNKT cells, producing iNKT cells for the rest of the animal’s life, which was generally about a year. Mice without the engineered stem cell transplants had undetectable levels of iNKT cells while those that received the engineered cells had iNKT cells make up as much as 60% of the total immune system cells. The team also found that the engineered iNKT cells were able to suppress tumor growth in both multiple myeloma and melanoma.
Dr. Yang, in a press release by UCLA health, discussed the significance of the results in this animal model and the enormous potential this could have for cancer patients.
“What’s really exciting is that we can give this treatment just once and it increases the number of iNKT cells to levels that can fight cancer for the lifetime of the animals.” said Yang.
In the same press release, Dr. Yang continued to highlight the study’s importance by saying that,
“One advantage of this approach is that it’s a one-time cell therapy that can provide patients with a lifelong supply of iNKT cells.”
Researchers mentioned that they could control total iNKT cell make up in the immune system depending on how they engineered the blood stem cells. However, more research is needed to determine how these engineered iNKT cells might be useful for treating cancer in humans and evaluating any long-term side effects associated with an increased number of these cells.
The full results of this study were published in the journal Cell Stem Cell.