Loic Deleyrolle

Activates T-Cell Recognition of Tumor-Initiating Stem Cells in Mouse Model of Glioma

This nanoparticle vaccine targets the slow-cycling, treatment-resistant, cancer stem cells to improve efficiency of anti-cancer drugs, thereby improving disease prognosis. Despite major developments in the field of anti-cancer therapies, tumor recurrence and metastasis after chemotherapy is still the major cause of cancer patient mortality. Although current RNA-lipid nanoparticle (NP) vaccines have shown promising results, they still remain encumbered by profound intra-tumoral and systemic immunosuppression. Because of the heterogeneity of cancer epitopes, a major challenge in the field of vaccine development is determining the best target. Studies carried out by our researchers at the University of Florida have demonstrated that recurrences in gliomas can be attributed to the subset of slowly dividing cells, resistant to conventional anti-cancer therapies. These slowly dividing cells exhibit enhanced tumorigenicity and infiltrative propensity. Hence, clinical strategies targeting this specific population of cancer cells holds great potential in improving therapeutic efficiency of drugs.

To address this issue of cancer recurrence, our scientists have developed a universal RNA-NP vaccine engineered with RNAs for epitopes specific to slow-cycling tumor cells, as well as a personalized RNA-NP vaccine engineered from RNA extracted from patient’s tumor biopsy. These vaccines are able to activate T-cell recognition of slow-cycling tumor-initiating stem cells mediating sustained anti-tumor activity in the mouse model of glioma.

Application

Nanoparticle vaccine for either personalized or universal treatment of cancer

Advantages

• Can be engineered using relevant tumor antigens, creating a universal RNA-NP vaccine to target treatment-resistant, slow-cycling cancer cells
• Can be engineered with RNA extracted from patient’s tumor biopsy, creating personalized RNA-NP vaccines
• Increased efficacy and specificity, generating robust and expeditious anti-tumor response
• Overcomes intra-tumoral and systemic immunosuppression, priming the system to respond better to immunotherapy

Technology

This therapeutic platform demonstrates the use of two different nanoparticle (NP) vaccines (personalized and universal) engineered with RNA derived from a specific subpopulation of slow-cycling, tumor-initiating stem cells. These immunomodulating vaccines are able to elicit T-cell response against slow-cycling, tumor-initiating cancer stem cells, leading to sustained anti-tumor activity. Researchers found that systemic administration of this vaccine primes the peripheral and intra-tumoral microenvironments for response to immunotherapy. These RNA-NPs localize to heart, lung, bone marrow, spleen, liver, kidney and subcutaneous/intracranial tumors. In immunologically resistant tumor models (i.e. B16F0, B16-F10, Lewis lung carcinoma) resistant to immune checkpoint inhibitors, these RNA-NPs activate the preponderance of systemic and intra-tumoral antigen presenting cells (characterized by co-expression of PD-L1 and CD86) for induction of anti-tumor immunity. Altogether, this therapeutic platform delivers specific sets of tumor RNA antigens purified from slow-cycling cancer stem cells to create personalized or universal vaccines.

Administration of Non-Toxic Compounds, in Combination with a Low Carbohydrate Diet, Aids in Cancer Treatment Without Negative Side Effects

This technology consists of natural compounds, which in combination with the implementation of a low carbohydrate diet, serve as a non-toxic aid in cancer treatment. Cancer is an energetically inefficient metabolic disease, with cancer cells needing high amounts of glucose to survive and multiply. Currently, most cancer treatments use toxic chemotherapeutic drugs to kill cancerous cells. While highly effective, chemotherapeutic drugs are nonspecific and have detrimental effects on non-cancerous cells as well as the target cancerous cells, leading to toxic side effects. Advancements are needed in improving the effect of current therapies on cancer cells and in reducing toxicity of current treatments. This technology limits proliferation of cancerous cells, thereby allowing current therapies to be more effective, without adding to toxicity of the therapy.

Researchers at the University of Florida have developed a nutraceutical formulation for aiding in cancer treatment. Four natural compounds, medium chain triglycerides (MCT), epigallocatechin-3-gallate (EGCG), curcumin, and sulforaphane (SFN), known individually for affecting cancer-signaling pathways, in combination with a low carbohydrate diet, interfere with the ability of cancer cells to proliferate and have significantly fewer side effects than chemotherapeutic cancer therapies.

Application

Non-toxic, natural compounds for slowing proliferation of cancerous cells during the treatment of cancer without contributing to chemotherapeutic toxicity

Advantages

• Therapeutic companion technology is non-toxic, and allows cancer therapies to be more effective
• Nutraceutical compounds are safe and well tolerated at effective doses, allowing for the combination of two or more in a single administration
• Technology is effective at slowing proliferation of tumor cells and increasing survival rates in multiple mouse cancer models, demonstrating utility across cancer types
• Studies with the combination of these four compounds in a mouse model of brain tumor are promising, demonstrating comparable results to treatment with standard of care as well as a synergistic effect when used in combination with standard of care

Technology

The natural compounds administered as part of this strategy for non-toxic treatment are medium chain triglycerides (MCT), epigallocatechin-3-gallate (EGCG), curcumin, and sulforaphane (SFN), alone or in any combination. MCTs are small molecules that quickly metabolize in the liver leading to an increase in blood ketone levels, reducing tumor cell proliferation, cancer progression, and extending life expectancy. EGCG, a green tea extract, downregulates tumor-promoting pathways. Curcumin has anti-inflammatory and anticancer effects, and SFN, found in high concentrations in broccoli sprouts, is an effective anticancer agent. These four natural compounds are non-toxic, along with a dietary intervention, can aid cancer treatments without contributing to toxicity of chemotherapies.

The administration of one or more natural compounds can be used alone or in combination with a ketogenic or modified ketogenic diet wherein carbohydrate intake is limited, which results in lower blood glucose levels, and limited glucose availability for tumor cell metabolism to fuel proliferation. This combined with the administration of the natural products described herein that affect cancer-related pathways, provides a safe, non-toxic, and effective therapeutic aid for cancer treatment.

Lessens Chemotherapeutic Side Effects through the Consumption of Natural Products

This natural formulation, optionally paired with a carbohydrate-limited diet, lessens the cytotoxic side effects of chemotherapy. Cancer management entails a combination of treatments, often employing surgery followed by chemotherapy, both targeted and non-targeted, with or without radiation. These procedures, particularly chemotherapy protocols, affect healthy cells as well as cancerous cells, resulting high toxicity leading to damage to critical organs, peripheral nerves, hematologic toxicity, fatigue, and anxiety or distress, among other negative effects. These negative side effects can become critical and result in the suspension of treatment, decreasing cancer treatment efficacy. Currently, few options are available to lessen the negative side effects of cancer treatments. Available therapies largely focus on treating specific problems associated with chemotherapy cytotoxicity rather than reducing the cytotoxic effect upon treatment.

Researchers at the University of Florida have designed a treatment strategy involving the oral consumption of four natural products, optionally paired with a carbohydrate-limited ketogenic or modified ketogenic diet, for safely attenuating the cytotoxic damage of chemotherapy cancer treatments. In pre-clinical model studies, the formulation of natural products protected normal cells, tissues, and organs from the undesirable side effects of cancer treatment such as anemia, peripheral neuropathy, neutropenia, and damage to essential organs, without affecting the efficacy of the chemotherapeutic agents.

Application

Consumption of the four natural products comprising this technology, curcumin, epigallocatechin-3-gallate (EGCG), glucosinolates (and/or derivatives thereof), and medium chain triglycerides (MCT), in formulated compositions, optionally with simultaneous with a reduction of carbohydrate intake, may safely reduce cytotoxic side effects associated with cancer treatments in patients

Advantages

• Improves resistance of normal cells in pre-clinical models to cytotoxicity of cancer treatments, reducing their negative side-effects
• Intended to prevent cytotoxic damage rather than treating a problem once it has already arisen
• Shows no signs of toxicity in pre-clinical models
• Could improves patient tolerance to chemotherapeutic toxicity, limiting or eliminating the need to reduce dosage or stop treatment

Technology

This technology, consisting of an oral formulation of four natural products, medium chain triglycerides (MCT), curcumin, epigallocatechin-3-gallate (EGCG), and glucosinolates, along with an optional low carbohydrate ketogenic or modified ketogenic diet, may mitigate the cytotoxic side effects associated with cancer treatments. Reduced carbohydrate intake reduces glucose levels, and consumption of MCT elevates blood ketone levels, mimicking the ketogenic diet, which has been hypothesized to attenuate chemotherapy-related toxicities. EGCG, a green tea extract, affects many pathways that can reduce the development of drug resistance and cancer robustness in tumor cells. Curcumin has anti-tumor, anti-oxidative, and anti-hepatotoxic activities, as well as neuroprotective effects. Sulforaphane (SFN), a glucoinolate in broccoli sprouts can modulate multiple cellular targets related to cancer development, as in animal models.1 Through the prevention of chemotherapy side effects, this technology allows chemotherapeutic cancer treatment to be maximally effective by eliminating the need to reduce dosage or even stop treatment due to toxic side effects.