The more than 100 ingenious scientists, physicians and other staff who are part of The Wanek Family Project for Type 1 Diabetes in the Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope are digging into the secrets of genetics, the immune system, beta cells and diabetic complications, united in pursuit of a singular ambition: curing type 1 diabetes.
The Wanek Family Project recently welcomed a new director, renowned type 1 diabetes scientist and physician Alberto Pugliese, M.D., who also serves as the Samuel Rahbar Endowed Chair in Diabetes & Drug Discovery and chair of the Department of Diabetes Immunology. Pugliese takes over from Debbie Thurmond, Ph.D., director of the Riggs and the Ruth B. & Robert K. Lanman Chair in Gene Regulation & Drug Discovery Research, who has served as interim director since December 2021.
“In my 35 years of type 1 diabetes research, I have seen amazing progress, at so many levels. I do want to share this notion with patients and their families, as the existence and impact of these discoveries may not be readily apparent outside the scientific community,” Pugliese said.
“In truth, research progress has been phenomenal. It is mind blowing what we have learned about type 1 diabetes that we did not know 30 years ago, or even 10, five or even one year ago. We now have better tools to advance new therapies and information that guides us toward which therapies should be tested — when, how, and in whom — depending on disease stage.”
As we celebrate this time of transition and opportunity, we asked research professor Enrique Montero, M.D., Ph.D., to reflect on some of the Wanek Family Project’s successes from the last year.
Montero is the scientific project lead on two major Wanek Family Project research programs related to type 1 diabetes. An expert in immunology and biotechnology, Montero first came to City of Hope in 2016 after developing immunotherapies for autoimmune diseases and cancer for more than 20 years in his native Cuba.
One of Montero’s studies focuses on engineering chimeric antigen receptors (CARs) in regulatory T cells, or CAR Tregs, which the immune system uses to prevent inflammation and potential reactions against normal cells and organs, such as the pancreas.
Regulating the Immune Response
“They are the peace officers in our body,” explained Montero, who has developed a novel approach to genetically engineer regulatory T cells to express an antibody with proven anti-inflammatory and immune-modulating properties to combine and increase the power of their individual effects in a single therapy. He says the approach represents an unprecedented strategy to re-educate an imbalanced immune system, with the potential to cure type 1 diabetes.
'It is mind blowing what we have learned about type 1 diabetes that we did not know 30 years ago, or even 10, five or even one year ago.'
Alberto Pugliese, M.D.
He plans to submit an investigational new drug application for approval by the Food and Drug Administration (FDA) so that he can start clinical trials of his CAR Tregs therapy as early as next year, which would be the first time the treatment is tested in the United States.
Like many projects at City of Hope, Montero says developing CAR Tregs has been a group effort from the start, utilizing experts from different fields.
With three GMP (good manufacturing practice) facilities on campus, covering all areas of cell and gene therapies, recombinant proteins and synthetic molecules, “We can go from drug development to clinical trials, which is what makes City of Hope unique,” he says. “That’s why I came to City of Hope, to be able to go from discovery to drug production to clinical application in patients.”
He is also leading a project developing single, bifunctional monoclonal antibodies, or bionics, to treat type 1 diabetes. Montero is redesigning antibodies he developed before joining City of Hope that are already on the market to treat other autoimmune diseases with the aim of generating a potent single-engineered molecule that combines immune intervention and regenerative medicine. The treatment, based on a medication already utilized for arthritis and psoriasis, as well as for certain COVID-19 patients, may also quiet the overwrought immune response in type 1 diabetes.
“What I did was take an antibody that has one function, regulation of autoimmunity, and insert another therapeutic molecule, so they will go together into the pancreas,” he explains. “Then, inside the pancreas, the antibody will release that molecule, kind of like when you have a spaceship, and it releases the capsule. That cargo will protect the insulin-producing cells and control the immune system.”
He says it took a big technological advance to combine the two molecules, but the new functionality should represent an amplification of positive immune responses to balance autoimmunity, quiet inflammation and improve distressed beta cell health and function.
“From my point of view, this product has the largest possible scope,” he says. “CAR Tregs can mainly be used at the start of the disease, but the bionic has a dual function: It will regulate the immune system, but will also rescue the insulin-producing cells. So, you can use it at the onset of the disease and in patients in which the disease has already been established for years. It can rescue those hiding beta cells and reinvigorate them.”
Montero says he and his team need to optimize the antibody by tweaking its formula, but that process should be completed in the next few months, after which he will pursue a clinical trial.
An ‘Inverse’ Vaccine
A novel immunotherapy trial that launched in 2020, but was delayed for nearly three years due to the COVID-19 pandemic, is now back on track. Known at the TolDC vaccine, this investigational treatment uses a patient’s own immune cells by removing a sample from the body, loading the cells up with vitamin D3 and a fragment of pro-insulin to help train the immune system to reduce inflammation, and injecting the modified immune cells back into the patient via a microneedle patch. Vitamin D3 is known to help regulate inflammation, so the hope is that, in combination with pro-insulin, the vaccine will help the body retain any beta cell function that still exists to keep the disease under control.
“The idea is to try to stop the progress at the onset of diabetes, stop the perpetuation of the disease,” Montero says.
The TolDC “inverse vaccine,” as it’s called — since the aim is to stop the immune response that leads to the death of insulin-making cells, rather than activating an immune response, which is the goal of most vaccines — was previously evaluated for safety and feasibility in Europe. Nine participants were monitored for six months after receiving the vaccine, and no signs of systemic immune suppression or major adverse reactions were seen. Furthermore, beta cell function and overall diabetic control remained stable, and patients maintained healthy blood sugar levels after treatment.
TolDC was identified by the Juvenile Diabetes Cure Alliance as one of only seven type 1 diabetes clinical trials in the United States that represents a “practical cure.” City of Hope’s trial will focus on newly diagnosed patients who still show beta cell function. Thus far, one patient has cells under production at City of Hope and is tentatively scheduled for injection by the end of the year. Another has been scheduled for blood collection and TolDC manufacturing.
In addition to the work being done to stop type 1 diabetes in progress, treatments for diabetes complications are also moving forward. A study supported by the late Arthur Riggs, Ph.D., led to the development of a product called LR-90 that could be a breakthrough for treating diabetic peripheral neuropathy, or nerve damage that can happen in diabetic patients, often in the hands and feet. City of Hope scientists reformulated it in 2021 to improve its performance, and preparations are being made to apply to the FDA for clinical trial approval.
“The transition that I'm expecting in the next year is that all of these drugs will begin the transformation from the science and discovery into a clinical application,” says Montero. “That's a real inflection point. And that's exactly where we are now, making sure these drugs can satisfy all the requirements from the regulatory authorities and so on. The expectation is that we will be able to jump into the clinical track for the realization of these drugs very soon.”
In addition to these four main clinical trial-track projects, innovative City of Hope investigators are busy exploring many paths forward in confronting type 1 diabetes, including immune modulation, beta cell expansion and replacement, prevention and reversal of diabetes complications, and development of novel biomarkers and imaging modalities for early detection.
“The Wanek Project is a fabulous resource, as it can promote creative and innovative research and approaches, especially in areas where philanthropic support can be applied in synergy with other resources to overcome obstacles and accelerate the pace of discovery and translation to patients,” Pugliese said. “Multidisciplinary approaches are needed to achieve the comprehensive and integrated understanding of the key factors leading to type 1 diabetes and to drive forward novel therapies that can benefit patients at any disease stage. I am excited by the opportunity to work together on a shared vision for a world-class type 1 diabetes program.”
City of Hope is joining with the Wanek Family and Ashley Furniture to raise awareness during National Diabetes Month. Click here to learn more.