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GenomeWeb - Christiana Care Preparing IND for CRISPR-Based Lung Cancer Therapy

Author: 
Christie Rizk

Christiana Care Health System's Gene Editing Institute is preparing to file an investigational new drug application (IND) with the US Food and Drug Administration for a clinical trial protocol that will use CRISPR genome editing to improve the efficacy of chemotherapy for KRAS-positive non-small-cell lung cancer (NSCLC) patients.

 

The protocol involves using CRISPR-Cas9 gene editing to knock down the nuclear factor erythroid 2-related factor (NRF2) gene — a master regulator of 100 to 200 genes involved in cellular responses to oxidative and/or electrophilic stress — in order to render patients more sensitive to chemotherapeutic agents such as cisplatin and carboplatin.


Researchers from the Gene Editing Institute published a proof-of-concept study in Molecular Therapy Oncolytics in December 2018 demonstrating that using CRISPR to disable NRF2 in lung cancer cells resulted in an increased sensitivity to chemotherapeutic agents in tissue cultures and reduced proliferation of the cancer cells. The researchers confirmed their observations in xenograft mouse models, where they found that homozygous knockout cells proliferated at a slower rate than the wild-type cells, even in the absence of treatment with chemotherapy.

 

While there is promising work going on to apply CRISPR in sickle-cell disease and cystic fibrosis, and combine it with targeted therapies to repair a gene, using CRISPR to disable a gene is a more viable near-term application, according to Eric Kmiec, director of the Gene Editing Institute. "[CRISPR's] natural function in bacterial cells is to destroy DNA or break it apart," Kmiec said. "So, the idea that we developed with a series of oncologists [at Christiana Care] was to knock out a particular gene that controls a lot of the chemo resistance in lung cancer patients."

 

The Gene Editing Institute researchers and their oncology colleagues chose lung cancer because it's the leading cause of cancer mortality in the US. The disease accounts for more than one in four cancer deaths, and kills more people than breast, prostate, and colon cancers combined.

 

And while multiple targeted therapies are now available for lung cancer, the drugs are indicated for a small subset of patients. For example, EGFR inhibitors are indicated for around 17 percent of patients with EGFR mutations, while ROS1 inhibitors are meant to treat around 1 percent of patients with ROS1 rearrangements. The CRISPR-based approach being proposed by Kmiec's group could potentially have wider utility.

 

Kmiec and his colleagues took advantage of previous research that had shown that disabling NRF2 could increase the efficacy of cisplatin and carboplatin. In the study, the authors noted that under normal conditions, the KEAP1 gene maintains low expression of NRF2, which regulates the expression of genes involved in protein degradation and detoxification. However, the stress exerted by chemotherapeutic agents triggers increased expression of NRF2, which in turn leads to increased resistance to treatment in cancer cells and induces cancer cell proliferation.

 

The researchers' idea, therefore, was to use CRISPR-Cas9 gene editing to disable NRF2 in lung cancer cells, rendering the gene incapable of producing a functional protein, and rendering those cells more sensitive to cisplatin, carboplatin, and vinorelbine (Navelbine). With NRF2 shut down, the genes responsible for the efflux of the anticancer drugs would not be activated, even under the most environmentally stressful conditions.

 

"What we brought to the table was a clinical perspective where we would use CRISPR in combination with standard therapies, to knock down the NRF2 function and therefore improve the capacity of chemotherapy to work," Kmiec said.

 

"There may be a T-cell therapy, a CAR T type therapy, for lung cancer, but there always will be a group of patients who are pretty refractory to all of the cool new drugs, whether it's T cells or onco-immunotherapy. So, it's a pretty dark picture and that's why we chose this area to work."

 

As of now, Kmiec added, the institute has completed animal studies and has engaged in conversations about next steps with the National Center for Advancing Translational Sciences. The institute has also had informal, but encouraging, conversations with the FDA that motivated the group to pursue a clinical trial for regulatory approval, he added.

 

If the institute is successful, this may be the first IND filed for a treatment that uses CRISPR in this way.

 

"There is a lot of excitement in terms of how [CRISPR] might apply to diseases like cancer where there are a lot of genetic alterations that may be responsible for growth — or in this case resistance — by using some of the auto-correct techniques within the cell that CRISPR can facilitate in order to confer responsiveness to an existing therapy," said Jeff Allen, president and CEO of the advocacy group Friends of Cancer Research. "I think this is an interesting application and I'm not aware offhand of any other attempts to do this that are quite this far along to the IND stage."

 

Allen also noted that although the vast majority of new INDs are still for traditional drugs, the FDA is receiving more applications for approval for therapy protocols or processes, similar to what Christiana Care is aiming to get approval for.

 

"I think particularly the biologics division of the FDA has been active in the development processes for some of these cell and gene therapy approaches [such as] CAR T therapy, where the process challenges associated with developing an individual cell therapy like that are as important, if not more important, than the actual gene target themselves," Allen said.

 

With CAR T and other similar therapies, which involve modifying a patient's own immune cells and reintroducing them back into the patient, there can be a lot of variability in the development process, he noted. So, the parameters of that process are overseen by the FDA and must be regularly reported back to the agency.

 

The Gene Editing Institute is now working closely with drug development consultancy firm Certara's regulatory science division, Synchrogenix, to formulate its IND application. According to Kmiec, the first application of this protocol will be in late-stage NSCLC patients who have stopped responding to traditional chemotherapy and are looking to salvage a few extra months of life.

 

But that amount of time isn't insignificant for patients or to many of the oncologists treating them.

 

 

"It's probably enough to see their children graduate from high school or to attend a wedding," Kmiec said. "It's almost like a compassionate approach, so it's a different way of thinking about using CRISPR."

 

Other details are still being worked out. For example, because NRF2 controls hundreds of genes, the FDA recommended that Kmiec and his team look into whether knocking it out could cause more problems than it solves.

 

"In a cancer cell that's operating incorrectly, I don't think that NRF2 inactivity would cause any other issues," he said. "But it's also plausible that if you knock it out in a normal cell, [the cell] could become more susceptible to stress …  and chemo is a great stressor. So, the downside of any treatment would be that the stress response would probably be negatively affected."

 

In order to suss this out, Kmiec and his team are looking at the effects of NRF2 knockdown in panels of primary lung cancer cells to see what other genes would be affected. They're still analyzing the data from those experiments.

 

"Of course, the goal would be to target tumor cells in a highly preferential way," he said, adding that his team is also working on targeting the treatment more precisely so that normal cells are not affected.

 

Though more work remains to be done, getting the protocol approved in late-stage patients first will likely actually help the researchers gather real-time data they need to refine the treatment, cut down toxicities, and design manufacturing processes that could facilitate development of a version of the protocol for earlier-stage cancer patients at some point in the future.

 

"These are very new technologies, and while they've been well characterized in different models, they haven't been as widely utilized in different human models. So, there's still a lot of learning going on for everyone," he said. "I think that for the short term, there will be a stepwise approach until these therapies have been better characterized."

 

What researchers can learn about these new treatments from patients who have no other therapeutic options — and therefore may have a certain willingness to take some risks with a new therapy — will contribute to the future development of both the therapies and their associated regulatory processes, he added.

 

In the longer term, the institute also has plans to experiment with knocking down NRF2 as a way to enhance chemotherapy or immunotherapy response in esophageal cancer, and is looking at using CRISPR to knock out KEAP1 as part of a treatment protocol for lung cancer. The researchers are also considering a different knock-out target as part of a pancreatic cancer treatment protocol, but the research is still in the early stages, and Kmiec declined to say which target he was considering.

 

In the shorter term, there are still several details that need to be worked out. Certain specifics of the protocol, including delivery of the CRISPR-Cas9 complex, have yet to be determined. "A major challenge of this particular approach is to target tumor cells directly in the patient and that's where we are hard at work," Kmiec said. With that in mind, the team is trying to determine whether the best mode of delivery would be ex vivo or in vivo.

 

And while the researchers' study showed that knock-down of NRF2 helped re-sensitize patients to treatment with cisplatin, carboplatin, and vinorelbine, specific chemotherapeutic agents haven't yet been written into the IND application as part of the protocol. "We would anticipate having it as a broad application in a small, restricted patient population," Kmiec noted.

 

The institute will likely have to contend with issues of patent protection, as well. The fight over the intellectual property rights to CRISPR technology has been ongoing for years. "We have put in place some IP protection covering the clinical process. It is difficult to know at this time about any issues related to patent protections for CRISPR overall," Kmiec said. "We have been talking to IP holders and will be more deeply engaged as we progress through the clinical development program. We do have a CRISPR license for certain nonclinical applications already."

 

The Gene Editing Institute is even looking to collaborate with partners in industry and academia in developing the CRISPR-based cancer treatment program.

 

"We're developing the clinical protocol and we hopefully will have smooth sailing," he added. "However, this is experimental medicine — we don't know what we don't know, and that's always a danger."

 

https://www.genomeweb.com/cancer/christiana-care-preparing-ind-crispr-ba...