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CAR T-Cells

Promising new solid tumor therapy

CAR T-cell (chimeric antigen receptor) therapy has emerged as a promising new therapy for treatment of cancer. The approach utilizes adoptive cell transfer, a technique in which T-cell isolated from a patient or from donor blood are expanded ex-vivo and modified to be more fit before reinfusion into the patient. In the case of CAR T-cells, they are genetically modified to express a chimeric antigen receptor which can have a variety of antigen targets. As opposed to its predecessor TCR ACT, CAR T-cells don't require MHC matching. The new CAR T-cells have been shown to be specific and efficacious in treatment of cancer. Several FDA approved treatments for hematological cancers already exist such as Yescarta (Axicabtagene ciloleucel) for treatment of refractory/relapsed large B-cell lymphoma. Solid cancers present a new issue, antigen selection.

Solid tumors make up approximately 90% of all adult human cancers and because of variety of premalignant tissues and oncogenic drivers there are thousands of antigens to target for therapy. Heterogeneity between cancer types and within the tumor makes finding an antigen target difficult. Traditional tumor associated antigens seem like a good target at first blush, but are complicated by their expression on healthy normal tissue. The CAR T-cells target both the heathy and malignant tissues resulting in on-target-off-tumor toxicity (OTOT). Neoantigens are a relatively recent CAR target and offer high immunogenicity, lack of OTOT toxicity, and higher affinity toward MHC. However, the most immunogenic neoantigens seem to be individual specific and vary from cancer to cancer. Therefore, neoantigen based CAR T-cell therapy would have to be tailored for each patient, adding to cost, complexity and time.

The Eil lab seeks to find a solution to OTOT toxicity and identify new antigens that could hold the key to treating solid tumors.

The recent development of a new type of cancer therapy involving the transfer of a patient’s own T cells that have been genetically engineered to recognize their cancer has produced remarkable results – curing patients of advanced cancer that previously were untreatable. This approach, using viral based engineering approaches to introduce a chimeric antigen receptor (CAR) into T cells, has met significant success in the setting of hematologic (liquid) malignancies. Fifty percent, or more, of patients with chemotherapy resistant lymphoma or myeloma receiving T cells genetically engineered to express a CAR targeting blood cancer antigens (i.e. CD19, BCMA) are rendered cancer free. However, the use of this technique has not been possible in solid cancers – which account for ninety percent of cancer related deaths in the United States. While T cell “dysfunction” can limit tumor destruction, the primary barrier preventing the use of CAR-T cells for the treatment of solid cancers remains the recognition of the ‘target’ on normal, healthy tissues – even at low levels of expression. In prior instances where genetically engineered T cells were used to treat solid cancers in humans, recognition of their target “off-tumor” produced unacceptable toxicities (death, severe colitis, blindness, hearing loss) – or no activity at all was appreciated.

As this “off-tumor” toxicity remains the primary barrier to the clinical application of CAR-T cell transfer for solid cancers (a potentially curative treatment), the Eil Lab is actively pursuing novel approaches to control the function of T cells outside of the tumor site. To date, this includes several ongoing projects that have seen rapid progress. We have generated multiple chimeric receptors independently in our lab along with validation of our approach to limit their function outside of the tumor site. While many investigators test their human CAR-T cells in immunodeficient mice, these systems are blind to “off-tumor” toxicities by design. As such, we have also developed a mouse model revolving around a CAR targeting a tumor antigen that is expressed in multiple visceral organ sites. We are actively using this model as platform to develop and test new strategies to control CAR-T function.

In concert, we have designed and validated a humanized chimeric receptor in tandem with safety strategies to limit off tumor toxicity. We are in the process of obtaining intellectual property protection for these inventions and aim to open an investigator initiated clinical trial in patients with cancer involving the liver within the next 12-18 months. This approach coalesces the clinical and scientific components of Dr. Eil’s expertise and aims to make tangible progress in patient outcomes.

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Updated 01/16/2024 15:02 PST