CAR T-Cell Therapy: Promising Results Against Small Cell Lung Cancer Renier Brentjens MD

By Reiner Brentjens, MD, PhD from Roswell Comprehensive Cancer Center

The basic platform on which we have been working for over two decades involves taking a patient’s own immune cells, T-cells, and genetically engineering them in the laboratory to express what we termed 15 years ago a CAR T-cell or chimeric antigen receptor.

A modified T-cell and a CAR are like Frankenstein-like molecules made up of a binding domain usually derived from a monoclonal antibody and the signaling domain of a T-cell receptor. When this molecule is expressed by the T-cell and engages the target being targeted, it activates the T-cell, which attacks the cell expressing that target. This has been pioneered and FDA-approved for a variety of blood cancers, including B-cell cancers such as lymphomas and leukemias that target CD19, expressed on the surface of B-cells and malignant B-cells, as well as multiple myeloma where the target is called BCMA and is expressed on myeloma cells.

The principle of this type of CAR T-cell therapy, with clinical efficacy already established, does not mean we cannot improve on current iterations of these CAR T-cells. However, it has been established that we can reeducate T-cells to recognize tumor cells and fully eradicate those tumor cells once the T-cells are infused back into the patient in a significant proportion of patients.

One of the major challenges facing the field is whether this technology can work only in blood cancers or whether the principle established in blood cancers can be extrapolated to much more common cancers like solid tumor malignancies.

Solid tumor malignancies are generally more challenging to treat with the immune system because they scaffold themselves with cells that suppress immune function, making it difficult for the immune system to recognize and attack them. Even if T-cells can recognize targets on the tumor cell surface, CAR T-cells may still ultimately fail because they encounter a very hostile suppressive immune microenvironment when they reach the tumor site. In this particular paper, we looked at a safe target called DLL3, which is expressed on neuroendocrine tumors, including small cell lung cancer.

Patients with small cell lung cancer typically have a poor prognosis, mainly due to the lack of effective therapies other than radiation and surgery in rare cases. Therefore, it is challenging to treat patients with advanced disease. We were inspired to look for targets on the surface of small cell lung cancer tumor cells, and DLL3 seemed to be an ideal target since it is predominantly expressed on these types of tumors and not on normal tissues.

In the laboratory, we worked on converting some binding domains and antibodies that recognize DLL3 into a chimeric antigen receptor. We examined a panel of 10 to 12 different binders and narrowed it down to two that seemed to be more effective than others when tested in vitro. We then conducted mouse experiments to determine which binder was better. Janneke Jaspers, a postdoc in our lab, led this research.

Out of these two receptors, one clearly stood out and we named it 16.8. I don’t think those numbers have any other meaning besides helping us identify 16.8 as the binder out of the twelve we initially looked at, which we moved forward with. As mentioned earlier, we now have a receptor that we can put in T-cells to recognize tumor cells in vitro.

The question then became how to move this forward, as we know that in real life, these tumors are surrounded by cells that suppress immune cells. One of the technologies we developed previously, which we published five to six years ago, is the ability to engineer T-cells not only to express the receptor but also to express other genes.

In this case, we looked at a pro-inflammatory cytokine called IL-18. CAR T-cells that have been additionally engineered with additional genes, including IL-18, are called armored CARs because we believe they are protected from the suppressive immune environment of the tumor.

This allows the cells to continue killing tumor cells when they reach the site of the tumor and to proliferate, creating more soldiers to attack the tumor cells. In this manuscript, we initially examined two different pro-inflammatory cytokines, IL-12 and IL-18.

We compared the two cytokines in mouse studies and found that IL-18 was superior. Therefore, we isolated the optimal receptor, which was IL-18. We conducted these studies in mice that have their own immune system, which better mimics what happens in patients. This is how we came up with the idea to use DLL3 targeted CAR T-cells that secrete IL-18. We are now very close to identifying the construct that we want to translate into the clinical setting.

Janneke conducted another interesting experiment. Some of you may be aware that immune checkpoint blockade is another way of modulating the immune system. Pembrolizumab is a drug that is now FDA approved and it blocks receptors on T-cells that can be inhibited when they come into contact with their ligand. Immune checkpoint blockade frees up immune cells within the tumor microenvironment, making it easier for them to fully eradicate the tumor.

The last experiment that Janneke conducted was to combine our now optimized DLL3-targeted CAR T-cells that secrete IL-18 with an antibody that blocks PD-1, an immune checkpoint. We are now mediating immune checkpoint blockade in the context of these optimized CAR T-cells.

The results showed that we could make what was already a very promising outcome in our mouse studies even more potent. As we finish up this body of work, our goal is to translate what we learned in mice and Petri dishes into the clinical setting. One advantage of moving from my old position to Roswell Park in Buffalo, New York is their strong dedication and track record in cell therapies.

Moving forward, we have identified the optimal construct, which are the genes we put into T-cells, and will put them into a virus that will infect the T-cells. Meanwhile, we are preparing an IND, which is an application to the FDA to get permission to run this clinical trial. We fully anticipate that in the next 6 to 12 months, we will be very close to being able to move this trial forward and treat the first patient with relapsed and refractory small cell lung cancer.

This work shows how we can translate research from the laboratory to the hospital and provide alternative options for patients who have a disease that is extremely difficult to treat, much less cure. Hopefully, the results we see in mice will be replicated in our patients.

 

Final thoughts about the New CART-Cell Strategy in Small Cell Lung Cancer

In closing, we are currently focused on a type of lung cancer that accounts for about 10 to 15% of all lung cancers, and we see this as a step in the right direction. If we can get this type of technology to work for a disease like small cell lung cancer, it will also give us insight into how to apply this approach to more common cancers such as breast cancer, prostate cancer, colon cancer, and others.

Although I’ve been working on this technology for 25 years, I really think we are at a watershed moment where we need to reevaluate our approach as medical oncologists and how we treat cancers. There are certainly some excellent chemotherapy regimens, surgeries, and radiation oncology approaches that cure many of our patients. However, this does not mean that we do not have a lot of work to do. In the past 50 years, we have primarily used chemotherapy, but over the last 20-25 years, we have started using different types of immune-based treatments in the clinic, including antibodies and bone marrow transplants, which are types of cell therapy. We are now at an exciting point in cancer research, especially in translational research, as we are getting better at harnessing the immune system. We know that properly prepared immune cells can enter the bloodstream, locate tumors, even small metastatic disease, and eradicate them. This means that it is a very exciting time for cancer research.

As someone working in the field, I am very excited about this time, and while this particular manuscript and focus of work are centered on small cell lung cancer, I feel confident that in 2 to 3 years, there will be clinical trials available with innovative approaches that will utilize this technology for every type of cancer imaginable.

I am an optimist, which is probably a good trait to have in this business. We have made remarkable leaps forward in the last 2 decades, and I think we are at an inflection point where progress will be made at a much faster and broader pace than in the past.

 

10 Key Takeaways from the CAR T-Cell Therapy Preclinical Trial

1. The preclinical study evaluated a new CAR T-cell therapy that targets a protein called ROR1, which is commonly found in many types of cancer cells.

2. The study was conducted using mice that were implanted with human cancer cells, and the results showed that the new CAR T-cell therapy was effective at reducing tumor growth.

3. The CAR T-cells used in the study were engineered to express a chimeric antigen receptor (CAR) that recognized and bound to ROR1 on cancer cells.

4. The CAR T-cells were also designed to secrete a cytokine called IL-12, which helps to activate other immune cells and enhance the anti-tumor response.

5. The study found that the CAR T-cell therapy was able to eliminate cancer cells in the mice, leading to a significant reduction in tumor size.

6. The therapy was also able to prevent the cancer from spreading to other organs in the body.

7. The CAR T-cell therapy was found to be safe and well-tolerated in the mice, with no evidence of toxicity or adverse effects.

8. The researchers suggest that the ROR1-targeting CAR T-cell therapy could be used to treat a wide range of cancer types, including breast, lung, and ovarian cancer.

9. The therapy could also be used in combination with other cancer treatments, such as chemotherapy or checkpoint inhibitors, to enhance their efficacy.

10. The results of this preclinical study provide promising evidence for the potential use of CAR T-cell therapy as a safe and effective cancer treatment in humans, and further clinical trials are needed to evaluate its efficacy in humans.

 

Renier Brentjens, MD, PhD – About The Author, Credentials, and Affiliations

Dr. Renier J. Brentjens is a prominent physician-scientist and leading authority in the field of cancer immunotherapy. He is currently affiliated with Roswell Park Comprehensive Cancer Center, a renowned institution dedicated to cancer research and treatment.

Dr. Brentjens has made significant contributions to the development of novel immunotherapeutic approaches, particularly in the area of CAR-T cell therapy. CAR-T cell therapy, or chimeric antigen receptor T-cell therapy, is a groundbreaking treatment that harnesses the power of a patient’s immune system to fight cancer.

Born and raised in the Netherlands, Dr. Brentjens pursued his medical education at the University of Amsterdam. After completing his medical degree, he embarked on a remarkable career in academic medicine and research.

Throughout his career, Dr. Brentjens has focused on exploring innovative strategies to combat cancer, particularly hematologic malignancies. His groundbreaking work has led to the development of CAR-T cell therapies targeting CD19, a protein expressed on the surface of certain types of cancer cells. These therapies have shown remarkable efficacy in clinical trials and have revolutionized the treatment landscape for patients with relapsed or refractory leukemia and lymphoma.

In addition to his clinical and research endeavors, Dr. Brentjens has been actively involved in mentoring and educating future generations of scientists and physicians. He has published numerous scientific papers and has been recognized with prestigious awards for his contributions to the field of cancer immunotherapy.

Dr. Brentjens’ dedication and groundbreaking research have not only advanced the field of cancer immunotherapy but have also provided hope and improved outcomes for countless patients facing life-threatening cancers. His relentless pursuit of innovative treatment strategies continues to inspire and drive progress in the fight against cancer.