CIRM-funded treatment for cancer granted FDA breakthrough therapy designation

Mark Chao, M.D., Ph.D., cofounder of Forty Seven, Inc. and current VP of oncology clinical research at Gilead Sciences

An antibody therapeutic, magrolimab, being tested for myelodysplastic syndrome (MDS), a group of cancers in which the bone marrow does not produce enough healthy blood cells , was granted breakthrough therapy designation with the Food and Drug Administration (FDA). 

Breakthrough therapy designations from the FDA are intended to help expedite the development of new treatments. They require preliminary clinical evidence that demonstrates that the treatment may have substantial improvement in comparison to therapy options currently available. CIRM funded a Phase 1b trial in MDS and acute myeloid leukemia (AML), another type of blood cancer, that provided the data on which the breakthrough therapy designation is based.

Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. Magrolimab works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.

Magrolimab was initially developed by a team led by Irv Weissman, M.D. at Stanford University with the support of CIRM awards. This led to the formation of Forty Seven, Inc., which was subsequently acquired by Gilead Sciences in April 2020 for $4.9 billion (learn more about other highlighted partnership events on CIRM’s Industry Alliance Program website by clicking here).

In CIRM’s 2019-2020 18-Month Report, Mark Chao, M.D., Ph.D.,  who co-founded Forty Seven, Inc. and currently serves as the VP of oncology clinical research at Gilead Sciences, credits CIRM with helping progress this treatment.

“CIRM’s support has been instrumental to our ability to rapidly progress Forty Seven’s CD47 antibody targeting approach.”

Magrolimab is currently being studied as a combination therapy with azacitidine, a chemotherapy drug, in a Phase 3 clinical trial in previously untreated higher risk MDS. This is one of the last steps before seeking FDA approval for widespread commercial use.

Merdad Parsey, MD, PhD, Chief Medical Officer at Gilead Sciences

In a press release, Merdad Parsey, M.D., Ph.D., Chief Medical Officer at Gilead Sciences discusses the significance of the designation from the FDA and the importance of the treatment.

“The Breakthrough Therapy designation recognizes the potential for magrolimab to help address a significant unmet medical need for people with MDS and underscores the transformative potential of Gilead’s immuno-oncology therapies in development.”

Therapy developed with CIRM award used in new clinical trial for COVID-19

Dr. Joshua Rhein, Assistant Professor of Medicine in the University of Minnesota Medical School’s Division of Infectious Diseases and International Medicine
Image Credit: University of Minnesota

While doctors are still trying to better understand how to treat some of the most severe cases of COVID-19, researchers are looking at their current scientific “toolkit” to see if any potential therapies for other diseases could also help treat patients with COVID-19. One example of this is a treatment developed by Fate Therapeutics called FT516, which received support in its early stages from a Late Stage Preclinical grant awarded by CIRM.

FT516 uses induced pluripotent stem cells (iPSCs), which are a kind of stem cell made from reprogrammed skin or blood cells. These newly made stem cells have the potential to become any kind of cell in the body. For FT516, iPSCs are transformed into natural killer (NK) cells, which are a type of white blood cell that are a vital part of the immune system and play a role in fighting off viral infections.

Prior to the coronavirus pandemic, FT516 was used in a clinical trial to treat patients with acute myeloid leukemia (AML) and B-cell lymphoma, which are two different kinds of blood cancer.

Due to the natural ability of NK cells to fight off viruses, it is believed that FT516 may also help play a role in diminishing viral replication of the novel coronavirus in COVID-19 patients. In fact, Fate Therapeutics, in partnership with the University of Minnesota, has treated their first COVID-19 patient with FT516 in a new clinical trial.

In a news release, Dr. Joshua Rhein, Physician at the University of Minnesota running the trial site, elaborates on how FT516 could help COVID-19 patients.

“The medical research community has been mobilized to meet the unique challenges that COVID-19 presents. There are limited treatment options for COVID-19, and we have been inundated daily with reports of varying quality describing the potential of numerous therapies. We know that NK cells play an important role in responding to SARS-CoV-2, the virus responsible for COVID-19, and that these cells often become depleted in infected patients. Our intent is to replenish NK cells in order to restore a functional immune system and directly target the virus.”

In its own response to the coronavirus pandemic, CIRM has funded three clinical trials as part of $5 million in emergency funding for COVID-19 related projects. They include the following: a convalescent plasma study conducted by Dr. John Zaia at City of Hope, a treatment for acute respiratory distress syndrome (a serious and lethal consequence of COVID-19) conducted by Dr. Michael Matthay at UCSF, and a study that also uses NK cells to treat COVID-19 patients conducted by Dr. Xiaokui Zhang at Celularity Inc.  Visit our dashboard page to learn more about these clinical projects.

CIRM funded clinical trial shows promising results for patients with blood cancers

An illustration of a macrophage, a vital part of the immune system, engulfing and destroying a cancer cell. Antibody 5F9 blocks a “don’t eat me” signal emitted from cancer cells.
Courtesy of Forty Seven, Inc.

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are both types of blood cancers that can be difficult to treat. CIRM is funding Forty Seven, Inc. to conduct a clinical trial to treat patients with these blood cancers with an antibody called 5F9. CIRM has also given multiple awards prior to the clinical trial to help in developing the antibody.

Cancer cells express a signal known as CD47, which sends a “don’t eat me” message to macrophages, which are white blood cells that are part of the immune system designed to “eat” and destroy unhealthy cells. The antibody works by blocking the signal, enabling the body’s own immune system to detect and destroy the cancer cells.

In a press release, Forty Seven, Inc. announced early clinical results from their CIRM funded trial using the antibody to treat patients with AML and MDS. Some patients received just the antibody while others received the antibody in combination with azacitidine, a chemotherapy drug used to treat these cancers.

Here is a synopsis of the trial:

  • 35 patients treated in a Phase 1 clinical trial have been evaluated for a response assessment to-date.
  • 10 of these have MDS or AML and only received the 5F9 antibody.
  • 11 of these have higher-risk MDS and received the 5F9 antibody along with the chemotherapy drug azacitidine.
  • 14 of these have untreated AML and received the 5F9 antibody along with the chemotherapy drug azacitidine.

For the 11 patients with higher-risk MDS treated with the antibody and chemotherapy, they found that:

  • All 11 patients achieved an objective response rate (ORR), meaning that there was a reduction in tumor burden of a predefined amount.
  • Six of these patients achieved a complete response (CR), indicating a disappearance of all signs of cancer in response to treatment.

For the 14 patients with untreated AML treated with the antibody and chemotherapy, they found that:

  • Nine of these patients achieved an ORR.
  • Five of these nine patients achieved a CR.
  • Two of these nine patients achieved a morphologic leukemia-free state (MLFS), indicating the disappearance of all cells with formal and structural characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment. 
  • The remaining five patients achieved stable disease (SD), meaning that the tumor is neither growing nor shrinking.

The results also showed that:

  • There was no evidence of increased toxicities when the antibody was used alongside the chemotherapy drugs, demonstrating tolerance and safety of the treatment.
  • No responding MDS or AML patient has relapsed or progressed on the antibody in combination with chemotherapy, with a median follow-up of 3.8 months.
  • The median time to response was rapid at 1.9 months.
  • Several patients have experienced deepening responses over time resulting in complete remissions. 

Based on the favorable results observed in this clinical trial to-date, expansion cohorts have been initiated, meaning that additional patients will be enrolled in a phase I trial. This will include patients with both higher-risk MDS and untreated AML as well as using the antibody in combination with chemotherapy.

In the press release, Dr. David Sallman, an investigator in the clinical trial, is quoted as saying,

“These new data for 5F9 show encouraging clinical activity in a broad population of patients with MDS and AML, who may be unfit for existing therapeutic options or at higher-risk for developing rapidly-advancing disease. Despite an evolving treatment landscape, physicians continue to seek new therapies for MDS and AML that can be used safely in combination with standard-of-care to help patients more rapidly achieve durable responses. To that end, I am excited to see meaningful clinical activity in a majority of patients treated with 5F9 in combination with azacitidine, with a median time to response of under two months and no relapses or progressions among responding patients.”

CIRM-supported study shows promise in fighting acute myeloid leukemia

Chemotherapy

Chemotherapy

For years chemotherapy has been a mainstay in the war against cancer. While it can be very effective it can also come with some nasty side effects. Since chemo works by killing rapidly growing cells, it not only hits the cancer cells, but can also hit other rapidly growing cells too, including those in our hair roots, which is why many people undergoing chemo lose their hair.

So, the key to a truly effective anti-cancer therapy is one that does as much damage as possible to the cancer cells, and as little as possible to all the healthy cells in the body. A therapy being developed by Cellerant Therapeutics seems to have found that sweet spot in a new therapy targeting acute myeloid leukemia (AML).

AML starts in the bone marrow and quickly moves into the blood, where it can spread to other parts of the body. It is the second most common form of leukemia and claims around 10,000 lives in the US every year. Chemotherapy is the main weapon used against AML but it can also cause nausea, hair loss and other complications and in most cases has limited effectiveness because, over time, the leukemia cells get used to it.

Cellerant 2013In a study published in the journal Blood Advances, Cellerant researchers explain the limitations of existing treatments.

“The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy.”

Cellerant has developed a therapy called CLT030 which targets CLL1, a marker found on the surface of leukemia cells but not on normal blood stem cells. Preclinical studies in mice show CLT030 is able to zero in on this surface marker and attack the leukemia but do little damage to blood or other surrounding cells.

In a news release, Ram Mandalam, President and CEO of Cellerant, said this is encouraging news:

“AML remains a significant unmet medical need, and our therapy, CLT030, that can target leukemic stem cells precisely while minimally affecting normal hematopoietic stem cells could improve outcomes while avoiding much of the toxicities associated with conventional chemotherapy and other targeted therapeutics.”

Mandalam says they are now doing the late-stage preclinical testing to be able to apply to the Food and Drug Administration for permission to start a clinical trial. CIRM is funding this stage of the research.