Severe Leukocyte Adhesion Deficiency-1 (LAD-1) is a rare condition that causes the immune system to malfunction and reduces its ability to fight off viruses and bacteria. Over time the repeated infections can take a heavy toll on the body and dramatically shorten a person’s life. But now a therapy, developed by Rocket Pharmaceuticals, is showing promise in helping people with this disorder.
The therapy, called RP-L201, targets white blood cells called neutrophils which ordinarily attack and destroy invading particles. In people with LAD-1 their neutrophils are dangerously low. That’s why the new data about this treatment is so encouraging.
“Patients with severe LAD-I have neutrophil CD18 expression of less than 2% of normal, with extremely high mortality in early childhood. In this first patient, an increase to 47% CD18 expression sustained over six months demonstrates that RP-L201 has the potential to correct the neutrophil deficiency that is the hallmark of LAD-I. We are also pleased with the continued visible improvement of multiple disease-related skin lesions. The second patient has recently been treated, and we look forward to completing the Phase 1 portion of the registrational trial for this program.”
The results were released at the 23rd Annual Meeting of the American Society of Gene and Cell Therapy.
The team took muscle progenitor cells – which show what’s happening in development before a baby is born – and compared them to muscle stem cells – which control muscle development after a baby is born. That enabled them to identify which genes are active at what stage of development.
In a news release, April Pyle, senior author of the paper, says this could open the door to new therapies for a variety of conditions:
“Muscle loss due to aging or disease is often the result of dysfunctional muscle stem cells. This map identifies the precise gene networks present in muscle progenitor and stem cells across development, which is essential to developing methods to generate these cells in a dish to treat muscle disorders.”
With more than 17,000 members from nearly 100 countries, the American Society of Hematology (ASH) is an organization composed of clinicians and scientists around the world working to conquer various blood diseases. Currently, they are having their 61st Annual ASH Meeting to highlight some of the exciting work going on in the field. Four of our CIRM funded trials have released promising results at this conference and we wanted to take the opportunity to highlight them below.
Sangamo Therapeutics is conducting a CIRM-funded clinical trial for beta-thalassemia, a severe form of anemia caused by mutations in the hemoglobin gene. The therapy Sangamo is testing takes a patient’s own blood stem cells and, using a gene-editing technology called zinc finger nuclease (ZFN), provides a functional copy of the hemoglobin gene. These modified cells are then given back to the patient. The company announced preliminary results from their first three patients treated. in the clinical trials at the ASH 2019 Conference as well.
Some of the highlights are the following:
The first three patients experienced prompt hematopoietic reconstitution, meaning that their supply of blood stem cells was restored.
The first three patients experienced no clonal hematopoiesis, meaning that the blood stem cells did not create cells with mutations in the DNA
Additional study results are expected in late 2020 once enrollment is complete and all six patients have longer follow-up
You can read more detailed results regarding the first three patients in the press release.
Forty Seven, Inc.
In another CIRM funded trial, Forty Seven, Inc. is testing a treatment for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The treatment involves an antibody called magrolimab in combination with the chemotherapy drug azacitidine. Cancer cells express a signal that send a “don’t eat me” message to 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 these evasive cancer cells. The goal is to use both magrolimab and azacitidine to make the cancer stem cells vulnerable to being attacked and destroyed by the immune system.
Of the 46 patients evaluated, 24 patients had untreated higher-risk MDS and 22 patients had untreated AML. None of the patients were eligible for treatment with chemotherapy.
In higher-risk MDS, the overall response rate (ORR), which is the proportion of patients in a trial whose tumor is destroyed or significantly reduced by a treatment, was 92%.
Within this group of patients with an ORR, the following was observed:
12 patients (50%) achieved a complete response (CR), meaning that they experienced a disappearance of all signs of cancer in response to treatment.
Two patients (8%) achieved hematologic (blood) improvement.
Additionally, two patients (8%) achieved stable disease, meaning the cancer is neither increasing nor decreasing in extent or severity.
In untreated AML, the ORR was 64% and the following was observed within this group patients with an ORR:
Nine patients (41%) achieved a CR
Three patients (14%) achieved a CR with an incomplete blood count recovery (CRi)
One patient (5%) achieved a morphologic leukemia-free state (MLFS), which is defined as the disappearance of all cells with morphologic characteristics of leukemia, accompanied by bone marrow recovery, in response to treatment.
Seven patients (32%) achieved stable disease (SD)
The median time to response among MDS and AML patients treated with the combination was 1.9 months.
More details regarding these results are available via the news release.
Onceternal Therapeutics, which is conducting a CIRM-funded trial for a treatment for lymphoma and leukemia, presented results at the 2019 ASH Meeting. The treatment involves an antibody called cirmtuzumab (named after yours truly) being used with a cancer fighting drug called ibrutinib. The antibody recognizes and attaches to a protein on the surface of cancer stem cells. This attachment disables the protein, which slows the growth of the leukemia and makes it more vulnerable to anti-cancer drugs.
Some of the results presented are summarized as follows:
Twenty-nine of the 34 patients achieved a response, for an overall best objective response rate of 85%.
One patient achieved a complete response (CR) and remained in remission six months after completion of the trial and discontinuation of all anti-CLL therapy. In addition, three patients met radiographic and hematologic response criteria for Clinical CR.
Five patients had stable disease.
The total clinical benefit rate was 100%.
None of the patients died or saw their disease progress.
Patients achieved responses rapidly, with 68% of patients achieving a clinical response by three months on the combination therapy.
The rise in leukemic cell counts that is typically seen in the first six months with ibrutinib by itself was blunted with the addition of cirmtuzumab, and leukemic cell counts returned toward baseline and normal levels rapidly.
Last, but not least, Rocket Pharmaceuticals presented results at the 2019 ASH Conference related to a CIRM-funded trial for Leukocyte Adhesion Deficiency-I (LAD-I), a rare pediatric disease caused by a mutation in a specific gene that affects the body’s ability to combat infections. As a result, there is low expression of neutrophil (CD18). The company is testing a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene. These modified stem cells are then reintroduced back into the patient. The goal is to establish functional immune cells, enabling the body to combat infections.
Here are some of the highlights from the presentation:
Initial results from the first pediatric patient treated demonstrate early evidence of safety and potential effectiveness.
The patient exhibited early signs of engraftment
The patient also displayed visible improvement of multiple disease-related skin lesions after receiving therapy
No safety issues related to administration have been identified
More detailed results on this trial are available via the news release.
governing Board of the California Institute for Regenerative Medicine (CIRM) awarded
two grants totaling $11.15 million to carry out two new clinical trials. These latest additions bring the total number
of CIRM funded clinical trials to 53.
$6.56 Million was awarded to Rocket Pharmaceuticals, Inc. to conduct a clinical trial for
treatment of infants with Leukocyte Adhesion Deficiency-I (LAD-I)
LAD-I is a rare pediatric disease caused a mutation in a specific gene that
affects the body’s ability to combat infections. As a result, infants with
severe LAD-I are often affected immediately after birth. During infancy, they
suffer from recurrent life-threatening bacterial and fungal infections that
respond poorly to antibiotics and require frequent hospitalizations. Those that survive infancy experience
recurrent severe infections, with mortality rates for severe LAD-I at 60-75%
prior to the age of two and survival very rare beyond the age of five.
Rocket Pharmaceuticals, Inc. will test a treatment that uses a patient’s own blood stem cells and inserts a functional version of the gene. These modified stem cells are then reintroduced back into the patient that would give rise to functional immune cells, thereby enabling the body to combat infections.
The award is in
the form of a CLIN2 grant, with the goal of conducting a clinical trial to
assess the safety and effectiveness of this treatment in patients with LAD-I.
utilizes a gene therapy approach, similar to that of three other clinical
trials funded by CIRM and conducted at UCLA by Dr. Don Kohn, for X-linked
Chronic Granulomatous Disease, an inherited immune deficiency “bubble baby”
disease known as ADA-SCID, and Sickle Cell Disease.
An additional $4.59 million was awarded to Dr.
Theodore Nowicki at UCLA to conduct a clinical trial for treatment of patients
with sarcomas and other advanced solid tumors. In 2018 alone, an
estimated 13,040 people were diagnosed with soft tissue sarcoma (STS) in the
United States, with approximately 5,150 deaths.
Standard of care treatment for sarcomas typically consists of surgery,
radiation, and chemotherapy, but patients with late stage or recurring tumor
growth have few options.
Dr. Nowicki and his team will genetically modify peripheral blood stem cells (PBSCs) and peripheral blood monocular cells (PBMCs) to target these solid tumors. The gene modified stem cells, which have the ability to self-renew, provide the potential for a durable effect.
This award is
also in the form of a CLIN2 grant, with the goal of conducting a clinical trial
to assess the safety of this rare solid tumor treatment.
“CIRM has funded 23 clinical stage programs utilizing cell and gene medicine approaches” says Maria T. Millan, M.D., the President and CEO of CIRM. “The addition of these two programs, one in immunodeficiency and the other for the treatment of malignancy, broaden the scope of unmet medical need we can impact with cell and gene therapeutic approaches.”