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Trial to assess CRISPR genome editing platform in non-small cell lung cancer

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Eric Kmiec



The Gene Editing Institute of the Helen F. Graham Cancer Center and Research Institute at Christiana Care has launched a clinical development program to assess the use of CRISPR gene editing technology for patients with KRAS- and PD-L1-positive non-small cell lung cancer.

Validated results from studies conducted in mice have laid the groundwork for the expansion of this approach to humans.

“We are hopeful that the results of our animal studies now enable us to take the next step in the FDA approval process for a cancer clinical trial using CRISPR,” Eric Kmiec, PhD, director of Christiana Care’s Gene Editing Institute, said in a press release. “It is an exciting journey. Our effort positions the Gene Editing Institute to bring this heralded technology to people who need it the most.”

Investigators will use the CRISPR genome editing platform to disable the nuclear factor erythroid 2-related factor (NRF2) gene, which is involved in tumor growth and resistance to chemotherapy. Investigators hypothesize that this approach will reduce tumor cell proliferation and make the tumor more susceptible to agents such as cisplatin and carboplatin.

HemOnc Today spoke with Kmiec about why no trials have been conducted using CRISPR in lung cancer, the challenges and goals of this trial, and the role of the FDA in this research.

Question: What prompted this study?

Answer: Lung cancer is the No. 1 cancer killer in Delaware and also the No. 1 cancer killer in the country. The Graham Cancer Center has been working hard to reduce cancer incidence and mortality in Delaware, so it made sense to target lung cancer. Nicholas J. Petrelli, MD, Bank of America Endowed Medical Director of the Graham Cancer Center, had become intrigued by the use of genomic medicine, which is so dominated by CRISPR. When Christiana Care embedded the Gene Editing Institute into Graham Cancer Center to develop innovative therapies, I asked Dr. Petrelli: ‘We have helped elucidate the regulation and mechanism of action of this breakthrough technology and we think we know how to use CRISPR, so what cancer should we target?’ He said he would like to tackle lung cancer. We then began working closely with Greg Masters, MD, principal investigator of the Graham Cancer Center’s NCI grant focused on lung cancer. We spent a lot of time talking with and listening to oncologists, some of whom were quite skeptical initially of the overall approach, but as more clinical evidence has become available, their skepticism has turned into hope. We did things in reverse from what most academics would do. We realized that we needed to ask physicians and practitioners how we could help them, rather than us telling them what we wanted to do. They encouraged us to develop a treatment for lung cancer that would lessen the impact of chemotherapy on their patients — which is how this all started.

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Q: Why haven’t there been trials for CRISPR in cancer?

A: Researchers in gene editing started out focusing on correcting inherited diseases, such as sickle cell disease and cystic fibrosis. Today, there is a lot of work taking place using CRISPR, including our work, but it is too early to see results. I expect we will see a number of clinical trials within the next year or so.

Q: How will you conduct the trial?

A: Our clinical trial will be among the first in the world, if not the first, to bring CRISPR to a solid tumor in humans. We will find out if CRISPR can reduce the size of the tumor through a direct injection into the tumor. Biopsies will be taken, and we might introduce CRISPR at the biopsy phase. Eventually, we can see our way to systemic delivery, but that needs more work and we probably will have a subsequent trial to evaluate the best method of delivery. The patients we are most interested in helping are those shown to be refractory to chemotherapy. A segment of this patient population, about 25%, receives no further treatment. We think a series of genes make cells resistant to chemotherapy, because these patients receive so much chemotherapy that the body thinks this is a stress point and shuts down. We are using CRISPR to knock out our first target gene, NRF2, so that the chemotherapy will be more effective. We also see a significant response when we simply disrupt NRF2 function with CRISPR in the absence of chemotherapy. There appears to be a synergistic effect, and we will follow the pattern of the single combinatorial therapy. The two important points are to keep the first trial reasonable in a proof of principle and to choose the patient population carefully.

Q: What do you hypothesize that you will find?

A: From our preliminary data, we believe CRISPR will reduce the tumor growth in a way that would be helpful to traditional therapeutics. Keeping our expectations modest, we are trying to augment a traditional therapy, chemotherapy, that works but also significantly affects a patient’s quality of life. We want CRISPR to be safe and cause no harm to the patient. We believe that if we can demonstrate this, a lot of others will follow suit. It is our hope that we can develop something that others can build upon and improve. We do not believe, and I hope we are proved wrong, that CRISPR itself is going to be a major complete treatment for any form of cancer.

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Q: What are the challenges and goals of this trial?

A: The major challenge is to have CRISPR work as efficiently as possible without any adverse events. This is a new field, and it has been remarkable how quickly the FDA and others have advanced this technology. The challenge of convincing regulatory agencies that this has a real possibility of helping people has been reduced significantly by people who have come before us. Another challenge is to determine how efficiently CRISPR will work in the tumor. We know that in some cases, remarkably, the target changes within the genomes of mutated cells have a different sequence than the genomes of normal cells. In the tumor cells we are studying, a new CRISPR cleavage site is created in the cell that allows us to develop a CRISPR package that should target only the tumor cell DNA and not the normal cell. We will look at the DNA sequence of an individual patient and use to our advantage the aggressive nature of how tumor cells grow.

We are looking at sequences from lung tumors vs. normal cells to see if there is a sequence for which we could design a specific CRISPR that will target the tumor cell DNA and not the normal cell. If we can find something like that, then this is a real breakthrough. Anyone with stage III lung cancer who is looking at 6 months more of life is probably not going to worry too much about offsite mutagenesis, and we want them to be able to live to see their daughter graduate or to have another birthday. We will design a trial and a therapy that has the patient in mind first, not just the success of the treatment. Our goal is to improve patient quality of life.

Q: What role will the FDA play in this?

A: The FDA is excited about human gene editing and wants to make sure that experimental medicine does not harm the patient. The FDA has encouraged several governmental agencies to form study groups, of which we are a part and that also include major pharmaceutical companies, to recommend how best to deal with human gene editing. The FDA is doing the right thing by engaging those who are moving toward clinical application and making sure that the right questions are asked. It is not clear what sort of test is needed to move things forward because the field is so new, but CRISPR is a very special technology that has not been seen in genetics before, and the FDA’s role will be to maximize safety and make sure patients are not knowingly treated with something that could cause them harm.

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Q: Is there anything else that you would like to mention?

A: We are the only gene editing institute embedded in an NCI community cancer center program in the nation. This provides us with a unique perspective and opportunity. We see why our work is so vital every day when we walk past patients with cancer coming to the institute for care. This work is not just life and death, it is about quality of life, too. Each day without a new treatment is a day that a mother, father or child deals with the terrible effects of chemotherapy. Although we are working to extend the gene editing strategies to cardiovascular and infectious diseases, the cancer targets are first in line. Because 85% of people in the United States receive their cancer care at a community cancer center, our diverse population will have access to this breakthrough technology immediately when treatments come online. We are building our treatment strategies around the patient and with the diversity of people in Delaware and the region in mind. – by Jennifer Southall

For more information:

Eric Kmiec, PhD, can be reached at Gene Editing Institute, Helen F. Graham Cancer Center and Research Institute, Christiana Care Health System, 4701 Ogletown Stanton Road, Newark, DE 19713; email: eric@geneeditinginstitute.com.

Disclosure: Kmiec reports no relevant financial disclosures.