MUSC startup Lipo-Immuno Tech awarded two STTR grants to bring novel cancer therapies to patients

MUSC startup Lipo-Immuno Tech LLC, was awarded two Small Business Technology Transfer (STTR) grants to support the commercialization of innovative cancer drugs. The company was founded in 2018 by immunologist Shikhar Mehrotra, Ph.D., and sphingolipid expert Besim Ogretmen, Ph.D., both MUSC Hollings Cancer Center researchers. Mehrotra and Ogretmen each got a $400,000 grant from the National Cancer Institute to help them with their feasibility studies for a year.

Lipo-Immuno Tech develops technologies related to lipids and immunology that can be used to make medicines to treat a wide range of diseases, including cancer. "Lipid metabolism plays an important role in many biological processes, including aging and disease. We are targeting lipid metabolism to enhance immunotherapy for more effective cancer control. We got our first company grant in 2020, and now with these two grants, we are a step closer to bringing these new options to patients," said Ogretmen, professor and the SmartState Endowed Chair in Lipidomics and Drug Discovery.

Mehrotra’s research is centered around the use of therapeutic T-cells to control tumor growth and autoimmunity. "Small business grants, like the STTR grant, are critical for helping us do the necessary validation experiments before clinical trials. Conventional research grants do not support that type of work," said Mehrotra, professor and scientific director of the FACT-accredited Center for Cellular Therapy at MUSC.

The current grants help to test two patented new ways to treat acute myeloid leukemia (AML), which is one of the deadliest cancers in the U.S. Despite new targeted therapies, overall survival is still poor for patients with AML. The researchers will use the validation studies to show that their innovative treatments could help future patients with AML and other cancers.

Targeting cancer cell mitochondria

Ogretmen is harnessing a recently identified weakness in cancer cells to kill tumor cells using a lipid-based drug. "It was not well-understood how mitochondria metabolism affects cancer cells. Mitochondria are structures in our cells that produce energy through a series of chemical reactions that make up our metabolism. Our mechanistic studies found that leukemia and some other cancers, like head and neck cancer, are very dependent on mitochondrial function, meaning that they cannot survive without their mitochondria," said Ogretmen.

"This is more of a targeted therapy, but instead of targeting a specific protein or pathway, this compound goes and kills the energy source for the cancer cells, the mitochondria."

Besim Ogretmen, Ph.D.

Ogretmen’s research team developed a new lipid-based drug based on the knowledge that most cancer cells have defects in their mitochondrial metabolism. These weaknesses cause the mitochondria of cancer cells to become more negatively charged than the mitochondria of healthy cells. The new ceramide-based lipid drug was modified to make it more positively charged, which makes it accumulate more in the negatively charged mitochondria that are specifically found in cancer cells.

The compound, LCL768, is unique because it can target cancer cells based on the chemical structures the researchers developed, significantly reducing the risk of harmful off-target effects.

"This is more of a targeted therapy, but instead of targeting a specific protein or pathway, this compound goes and kills the energy source for the cancer cells, the mitochondria. No other drugs that are currently on the market act in the same way. This means that we can actually kill and inhibit cancer growth," said Ogretmen, who is collaborating with AML experts at MD Anderson Cancer Center. This study will test how LCL768 selectively causes mitophagy-dependent cell death in various humanized animal models of AML. Mitophagy is a cellular process that eliminates damaged mitochondria.

Overcoming oxidative stress to boost anti-cancer T-cells

The tumor microenvironment is often unfriendly to tumor-killing T-cells, lowering the effectiveness of T-cell therapy. Mehrotra and his team have found a way to overcome oxidative stress – an imbalance between free radicals and antioxidants – in the tumor environment to support T-cells.

Mehrotra previously discovered that a specific type of T-cell, known as long-lived central memory T-cells, had a high antioxidant capacity, which correlated with their long survival and tumor-killing ability. These cells also had a uniquely high expression of a molecule called thioredoxin-1 on their cell surface. "Long-term survival is a big problem in adoptive cell transfer, and our data showed that thioredoxin-1 may be a key to increasing T-cell persistence in the oxidative tumor microenvironment," said Mehrotra.

The initial data was generated using genetic mouse models for proof of concept, but now the team has shown that adding thioredoxin to human T-cells that have been removed from a patient increases their tumor-killing potential in cell culture. Mehrotra will use the phase I funding to test the tumor-control capacity of human T-cells programmed with recombinant thioredoxin in xenograft mouse models with human cancer cells.

Generating tumor-specific central memory T-cells for adoptive cell transfer is prohibitively expensive, which is why this approach is not currently used clinically. However, Mehrotra’s approach may decrease the cost and make this treatment feasible. "Recombinant thioredoxin is readily available, so theoretically, this approach can be used to program generic T-cells into billions of central memory T-cells and preserve this phenotype long after the rapid expansion protocol," said Mehrotra, who will be validating this patented approach in MUSC’s FDA-registered Current Good Manufacturing Practice (cGMP) Center for Cellular Therapy.

Leveraging academic opportunities for entrepreneurial development

Both Mehrotra and Ogretmen credit the pilot grants from Hollings, NIH funding and the collaborative research environment at Hollings for the data that have led to these ongoing commercialization processes.

"We are driven to move our findings from the lab bench to the patients. However, to get to that side of the story, there are many entrepreneurial activities, including layers of grants and funding that accompany commercialization," said Ogretmen.

 

Both grants use patented processes and compounds, and the researchers leaned heavily on MUSC’s Zucker Institute for Innovation Commercialization for support to ensure that everything was set up correctly. Mehrotra said that MUSC’s structure for entrepreneurial activity provides them with the means of connecting with other people who can move their discoveries further along the drug discovery pipeline.

Lipo-Immuno Tech’s founders plan to apply for phase II funding later this year, which will support more commercialization and Investigational New Drug (IND)-enabling studies for clinical trials. They credit MUSC’s and Hollings’ leadership, which supports and encourages these entrepreneurial activities. The Hollings Shared Resources, supported by an NCI Cancer Center support grant, are fundamental for many researchers across the institution.

"We couldn’t do this research without the core facilities," said Mehrotra. "The Lipidomics Shared Resource played a big role in developing and synthesizing the LCL768, and my experiments frequently use the Flow Cytometry and Bioenergetics Profiling Shared Resources. Also, the Center for Cellular Therapy, which is dedicated to supporting investigator-initiated clinical trials involving cellular therapy, will be a huge asset to our phase I and phase II validation studies." 

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