Gene Editing May Improve QoL With Standard of Care Therapy in Hematologic Malignancies

Eric Kmiec, PhD

Eric Kmiec, PhD

CRISPR, the gene-editing tool, has been introduced to the treatment landscape for patients with hematologic and inherited diseases after providing evidence that it can help improve outcomes with standard of care therapy, according to Eric Kmiec, PhD.

At the24^thAnnual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma, the role of CRISPR and how its applications can be applied to cancer therapies was discussed in a presentation. Similar to immunotherapy, T cells can be extracted from the body and programmed to attack the tumor cells on their own. In patients who are resistant to standard of care therapies, such as chemotherapy, CRISPR may be able to help overcome resistance in select patient populations.

“My opinion is that CRISPR will augment standard of care therapy for cancer that is already there,” said Kmiec. “We don’t have to reinvent the wheel. We just need to make it turn quicker and move more effectively.”

Although this is a breakthrough technology that is transforming outcomes in patients with cancer, the approach may have off-target effects. However, more research may provide hope for this therapy in the future for the treatment of patients with both liquid tumors and solid tumors.

In an interview withTargeted Oncology, Kmiec, director, Gene Editing Institute, Christiana Care, discussed the evolution of CRISPR and how it fits into the treatment landscape for physicians in the community practice. He highlights the challenges that arise with the use of CRISPR and how to address these issues.

TARGETED ONCOLOGY: Could you provide an overview of what was discussed at the meeting?

Kmiec:The talk started off primarily by discussing that CRISPR is a dynamic technology that is a breakthrough technology that comes along maybe once a decade. It has revolutionized the way we do genetics at every level. While most of us want to utilize it in therapy for cancer and inherited disease, it has actually had quite an impact already in drug discovery and monitoring and identifying new targets for drugs for cancer and the immune cells. The advance is that this is a naturally occurring process that has been found in just about every bacterial species where it has been looked for. That process enables us to make an incision very precisely in the human genome using this genetic tool and tell the body where to repair itself or where to disable a specific gene.

TARGETED ONCOLOGY: What are the scientific strategies and approaches to using CRISPR?

Kmiec:The use of CRISPR now is to utilize it to make a specific cut in genomic DNA, and there are a couple of outcomes. For many cancers, the use of CRISPR is to primarily disable the gene that is enabling the cancer to grow more aggressively. We see this with its work in T cells, where T cells are being modified. Your own T cells are taken out of the body, modified, and then returned to the body to enhance the fighting capacity against tumors. When a tumor develops in the body, the body’s immune system responds, and the T cells are at the forefront of that.

What has been happening over the last 5 to 6 years is people have been trying to reengineer T cells to make them even greater more aggressive fighters against tumors. Some of that is on the basis of what we now call immunotherapy where we are redirecting the body’s immune system to fight off the tumor. So far, for liquid tumors and the so-called CAR T-cell therapy, that has been working pretty well. We are now starting to see some side effects of this in some people because as you could imagine if you could alter your immune system in any way, the body will respond negatively. That is the first round, but there are clinical trials already with that approach underway in humans. It is astonishing, and that is what gives CRISPR such a remarkable name because it has moved so quickly into humans.

The other side, which is approach we use, is to use CRISPR to disable genes that are essentially blocking the effectiveness of the standard of care. For example, in lung cancer, the body is not in favor of chemotherapy or radiation therapy. The first-line of defense for most solid tumors, like lung cancer, is still chemotherapy. These chemotherapy regimens were developed in the 1970s, and it’s effective nondiscriminatory killing. Tumor cells and normal cells are both killed, and as a function of that, there is a great deal of toxicity that is associated with chemotherapy. If you speak with patients on chemotherapy, they start to get a little more depressed over time because the side effects they deal with make them so sick that they feel it’s worse than the disease itself. Of course, it’s not, but the feeling is.

We now know, and this has actually been known for close to 10 years, many of the genes that enable the body to develop resistance to chemotherapy. It’s a vicious cycle. Once the chemotherapy starts, it is effective, but the tumors cells develop a resistance to it so that at some point during the chemotherapeutic treatment, the tumor cells become resistant, and all you are basically doing is pumping in more and more chemotherapy as the patient just gets sick and sicker. Meanwhile, the tumor basically stays the same.

What we have done is designed a new approach, primarily for solid tumors, where we disable a series of genes that are preventing chemotherapy from working. In other words, we are knocking out the chemotherapy-resistant genes. It started about 2 and a half years ago, more as a general approach or therapeutic strategy. Now it has gained a fair bit of momentum because if you can do that specifically, you are not really pushing for cure, which is out of sight, and you are not even making overhyped promises, which often happens and is true of all technologies. We set our goals based on the patient needs, which is to make their quality of life better. We are trying to help standard of care therapies that we know works but when it fails to work, it makes people ill. Our goal is to make it more effective so people can tolerate the therapies.

TARGETED ONCOLOGY: How has CRISPR been implemented into your institution?

Kmiec:All of this is driven primarily by our commitment at Christiana Care to view the patient first, not the technology. There are very powerful and outstanding research groups around the country who are working on this technology and making it more efficient and precise. That is so great, and we contribute to that too. However, we are a community cancer center, and the difference in this situation is because a lot of the folks who walk through our doors have never been on a clinical trial, oftentimes are the sociodemographics that does not participate in clinical trials, and often times do not understand what these breakthrough technologies mean.

We choose our path based on what the patient really needs in cancer therapy as opposed to what we think is required. This is a little bit of an attitude, but we think it is the right one to do. Our patient-first approach has gained a lot of attraction as well because cancer is so complicated. So many smart people have worked on this for so many years, but we still have major challenges. We are trying to utilize CRISPR to help standard of care therapy work better in a way that can help the patient’s quality of life.

TARGETED ONCOLOGY: Are there any specific malignancies in which this technology is particularly useful?

Kmiec:CRISPR and gene editing have been major components of therapy in lymphoma and T cell leukemia. Why is that the case there? We can actually remove the T cells or immune cells from the body, treat them outside the body and put them back in. This is like a bone marrow transplant where they modify the cells and put them back in. It makes perfect sense, it is the right thing to do, but we are beginning to see any sort of modification of T cells that has the ability to attack and cause autoimmune killing could cause some issues in the body. There has been a couple of cases where there has been something called a cytokine explosion or cytokine attack. Although it hasn’t had any negative impacts, at some point the body is still going to recognize modified T cells that have been taken out and become foreign, but as I said, there’s a lot of things in cancer that are going wrong, and any help is great. That has really been pioneering work, and there is a series of clinical trials for patients with leukemias and lymphomas that are either already active or are currently recruiting that have made it through the FDA. That is currently where this is in humans.

TARGETED ONCOLOGY: What are the challenges with CRISPR applications, and how might we be able to address these issues?

Kmiec:The most common criticism of CRISPR is that it will act at other places than it’s designed to act in a human genome. If I design disabled gene X because gene X is contributing to the chemotherapy resistance of lung cancer, it will act very efficiently in gene X. In fact, it is frighteningly efficient. However, it may also act at gene Y at a lower, nonspecific or off-target effect. That can happen, but I think that is a part of nature. Nothing in nature is perfect, so I think the major criticism of CRISPR in general is it’s not going to act at only 1 site.

We have had a couple of these explosions in the media about 2 years ago. People reported that CRISPR targeting was activating these tumor suppressor genes, it turned out none of that activity caused any secondary tumors.

We address that primarily by using our patients-first approach in patients who have very few choices left. In someone who is 53 years old with stage III lung cancer inevitably, this is inevitably going to be a real uphill battle. We are trying to develop a protocol that will allow them 3 to 6 extra months of life so they can get to a birthday or see a daughter graduate from high school or college. Our approach is reasonable, and I think if we keep that approach reasonable, then I think we can actually have a bit of success.

Why is that related to outside immunogenetics? In that case, someone who is going to be surviving 3 to 6 months is probably not as concerned with off-target effects because they take so long to come out, if they ever occur. We address those criticisms by primarily choosing carefully the patients we can help as opposed to making blanket statements. Off-target effects can be detrimental and devastating to children. In cases where childhood cancer is being treated with CRISPR and gene editing, that may be a bit of a problem because we may not see any effect for 10 to 15 years, but suddenly something that was made cryptically could begin to emerge. That is my biggest fear, that we go into pediatric cases with CRISPR, but we don’t know what we don’t know. Treating childhood cancers or even genetic diseases like sickle cell disease, these things with this off-target immunogenetics may have a downstream effect. Off-target stuff comes to the forefront most of the time.

Our greatest challenge for any solid tumor work is how to deliver CRISPR to the tumor cell. That is a major challenge. We have not been able to develop a way to inject systemically any biotherapeutic and have it go specifically to the tumor cells and not normal cells.

Despite many claims to the contrary, I think everyone who has claimed that might keep it out of their [reach]. However, that is also a bit of a challenge. How can we get CRISPR to work on only tumor cells? We discovered strangely enough in 1 form of lung cancer called squamous cell carcinoma, a certain parentage of the patients actually have a unique site in their DNA that has occurred because there is a tumor, so it has only occurred because there is a tumor, tumor cell DNA where the CRISPR will work. The tumor cell develops its own selective target to put CRISPR to work. We are looking at ways in which we can inject the CRISPR particle into the organ so that it will penetrate to all of these cells but will only work in the tumor cell DNA. We use the evolution of tumor cells to fight against itself. That is how we are getting around selectivity. Off-target immunogenetics and penetration are the 2 big challenges, and those are the ways in how we are personally dealing with them.

TARGETED ONCOLOGY: How do you think this technology can revolutionize cancer treatment?

Kmiec:I have been running a discovery research lab my entire career primarily in universities, and I moved to the community cancer center because I became friends with a medical director who told me I wouldn’t understand cancer unless I was embedded in a hospital or treatment center and taught organically to oncologists who see patients. He was right, and I think what is required for us and how we can affect cancer therapy is actually to engage with oncologists and ask them [questions] in a bottom-up approach. How can we bring a breakthrough technology into your world? Many of my colleagues do the reverse; they say they are going to develop a breakthrough technology, and we are going to hand it down from the mountain so that everybody can use it. I think that is the wrong approach.

I have been fortunate enough to engage with a number of community oncologists. They ground us, they educate us on what they really need, and a colleague and I decided how it will affect cancer. My opinion is that CRISPR will augment standard of care therapy for cancer that is already there. We don’t have to reinvent the wheel. We just need to make it more effective, turn quicker, and move more effectively. That is the way CRISPR can help in the next 5 to 10 years.

After that and further technology development, who know what will happen next? I think we have to work within the confines of what community cancer centers and oncologists tell us in terms of where we can help them. They lead charge, and we develop the technology around their ideas as opposed to the reverse.