Project title: Personalized Immunotherapy for Atypical Pulmonary Carcinoids

Description

Dr. McHugh and his research team are developing a personalized immunotherapeutic platform to treat atypical pulmonary carcinoids.

What critical NET problem/question will researchers try to answer?

The research team will explore whether atypical pulmonary carcinoids can be selectively targeted and killed through the recognition of cancer-specific mutations.

Why is this important?

Patients who have metastatic neuroendocrine tumors currently face an extremely poor prognosis. Surgical resection of part of the lung, or an entire lung, can be effective in some patients while the disease remains localized; however, this procedure inherently decreases lung function and is not effective for tumors that have already spread to other parts of the body.

What will the researchers do?

McHugh and his team will employ genome-editing tools that uniquely recognize cancer cells based on mutations found in each individual patient’s cancer. Based on this highly specific recognition process, cancer cells will be selectively killed, triggering a systemic anti-cancer response.

How might this improve treatment of NETs?

This research aims to develop a personalized therapy that is both highly effective and minimally harmful to normal tissues. Whereas current treatment options and emerging options for other cancers have substantial drawbacks—including severe side effects and cancer recurrence—the  personalization offered by this therapy enables it to be both highly targeted and broadly useful to patients who have atypical pulmonary carcinoids and neuroendocrine tumors in general. This therapy also has the potential to be comparatively non-invasive and inexpensive, making it accessible to many patients worldwide.

What is the next step?

As a pilot study, this therapy is still in its early stages of development; however, the next step in this project is to demonstrate efficacy in mouse models and patient-derived primary cancer cells to motivate subsequent clinical trials. The long-term goal of this research is to develop a personalized therapeutic pipeline that can be readily accessed by clinicians.

Outcomes:

This project aims to develop a novel therapeutic approach to treating neuroendocrine tumors (NETs) based on a method that specifically targets cancer-driving mutations. Doing this in a personalized manner enables us to destroy NETs without significant toxicity to other tissues because the mutations are uniquely present cancer cells. This approach uses Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR), a genome-editing technique to selectively cut the cancer cell genome at the site of a mutation while leaving the DNA of normal cells intact. This selective cutting enables co-delivered DNA to integrate into the cancer cell genome. Once this occurs, the cancer cell will produce the protein encoded by the DNA we are inserting, which subsequently kills the cell.

Given the recent clinical successes of cancer immunotherapies, we have also integrated a second cancer cell killing mechanism, which leverages the ability to not only kill cells with this protein, but also elicit a robust anti-tumor response to kill cancer cells throughout the body that have similar characteristics to the cells that were directly killed. Because the key to this therapy outperforming current NET treatments is its potentially unprecedented selectivity and oncogenic mutations are often small despite the major ramifications they have downstream, we must engineer our targeting system to use the most specific version of targeting that will enable it to distinguish normal DNA from DNA containing the target oncogenic mutation.

Our progress to date includes the optimization of delivery to a pulmonary NET cell line, which is critical in achieving a robust immune response, the identification of hotspot mutations in those cells, the production of formulations targeting one of those mutations, and the demonstration of selective cell killing in those cells. To demonstrate the exceptional selectivity of this therapy for cells based on the presence of cancerous mutations, we have also engineered a pulmonary NET cell line to create a testbed in which cells are identical aside from a single oncogenic mutation, showing the ability to insert a gene specifically into the target cell and, importantly, not into the cell with a sequence that differs by only one base pair.

The most exciting results we have obtained show that our system has the ability to kill a pulmonary NET cell line while avoiding killing another cell line lacking the target mutation. After designing the components necessary for highly specific mutation targeting and cell death induction via diphtheria toxin subunit A production following DNA integration, we treated cells with the formulation and waited to examine their relative levels of cell death. Mutation-mediated DT-A insertion induced cell death in pulmonary NET cells harboring the target mutation while inducing no cell death above background in cancer cells lacking the mutation, underscoring the exceptional specificity of this approach, even when the difference between the target and wildtype sequence is only one base pair—a circumstance that very closely mimic clinical disease.

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