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How Ultrahigh-Dose Radiation Therapy, Interferon, and CAR T Cells May Boost Immunotherapy Effectiveness


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This past June, the University of Pennsylvania established the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation to study the role interferon and pattern recognition receptor signaling transduction pathways play in modulating the immune system’s ability to recognize and destroy cancer cells. Initially, the center is launching a series of preclinical studies investigating how these pathways can impact the immune system against cancer, especially in combination with immunotherapies, such as immune checkpoint blockade. In addition to understanding their biologic regulation and mechanism, the center will investigate therapeutic approaches that manipulate these pathways to enhance the immune response against tumors. These studies include the use of FLASH-RT—a new type of ultrahigh-dose radiation that can deliver a course of radiation that typically spans several weeks in less than 1 second—and how the therapy can activate interferon pathways and help the immune system attack cancer cells more effectively, especially when used in combination with immunotherapies. A second approach being investigated is the use of specifically engineered chimeric antigen receptor (CAR) T cells to influence the interferon signaling pathway in the tumor.

Andy J. Minn, MD, PhD

Andy J. Minn, MD, PhD

The ASCO Post talked with Andy J. Minn, MD, PhD, Associate Professor of Radiation Oncology at the Perelman School of Medicine at the University of Pennsylvania and Director of the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation at the Abramson Cancer Center, about how these laboratory studies may improve the effectiveness of cancer immunotherapy and potentially change treatment paradigms.

Signaling Pathways, the Immune System, and Cancer

Tell us about the impetus for launching the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation.

Over the past several years, the work across many research laboratories at the University of Pennsylvania has been heavily focused on how to make immunotherapy more effective for patients with cancer. My laboratory has been particularly interested in understanding the relationship between the interferon pathway and cancer. We became interested in this pathway because, many years ago, we made the observation that the expression of interferon pathway–related genes is pervasive across human cancers. This was our first insight into the hypothesis that the interferon pathway and the signaling pathways that activate it, such as pattern recognition receptors, might be important in influencing the progression of cancer or the response to cancer therapy.

Over the years, we have discovered that this pathway can, in fact, regulate metastasis, therapy resistance, and whether the immune system is able to perceive and attack the tumor. In this era of immunotherapy, we believe it is particularly important to understand this latter connection among interferon signaling, cancer, and the immune system. Could this interferon pathway help immunotherapies recognize and destroy cancer cells, or might it be corrupted by cancer cells to interfere with the effectiveness of immunotherapies? It turns out the answer to both questions is yes.

Given the concentration of multiple talented researchers at Penn interested in understanding, dissecting, and therapeutically leveraging the multifaceted properties of this pathway in cancer, we thought that a center that could nucleate these scientists and this interest could have enormous potential.

The new center will focus on understanding the complexities of the interferon pathway, the biology that impacts its function, and therapeutic approaches that exploit its influence over the antitumor immune response. For example, one of the unexpected observations by many groups over the past several years is that many cancer therapies, even the conventional ones such as chemotherapy, radiation, and targeted agents, can activate interferon and pattern recognition receptor pathways. What we believe is happening is that the effects of these therapies on cancer cells can mimic aspects of a viral infection, which is typically how interferon pathways are activated. Thus, part of the research at the new center will be to mechanistically understand how this is happening and then learn how best to control the pathway to enhance immunotherapy.

Using Radiation to Make Cancer Susceptible to the Immune System

Two of the research projects at the Mark Foundation Center are focusing on comparing how FLASH radiotherapy versus conventional radiotherapy might impact the interferon and pattern recognition receptor pathways to enhance the immune system to attack malignant tumors. How might FLASH radiation therapy make a tumor more susceptible to the immune system?

These projects build on the idea that radiation can activate interferon pathways in a favorable way that can cause the tumor to respond to an attack by the immune system, particularly in combination with immunotherapies.1,2 Mouse models of cancer are showing that FLASH radiation is tolerable, but the biologic effects are poorly understood. The field is diligently pursuing what happens to tumors and normal tissue when highly concentrated doses of radiation are delivered. The research is still limited to preclinical models, but the ability to kill tumors appears comparable between FLASH and conventional radiation, whereas the normal tissue effects appear to be dramatically different.3

One normal tissue is, of course, the immune system. Since FLASH radiation, like conventional radiation, can activate interferon pathways, we are testing whether there are important differences in the way it activates the immune system and how this might impact the effectiveness of immunotherapies.

“The ability to kill tumors appears comparable between FLASH and conventional radiation, whereas the normal tissue effects appear to be dramatically different.”
— Andy J. Minn, MD, PhD

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Rare Opportunity to Reduce Toxicity

What are the side effects of delivering such highly concentrated amounts of radiation in seconds rather than over the course of many weeks?

Based on the studies so far in preclinical mouse models, the toxicity can be significantly less than with traditional radiotherapy.4 This is a rare opportunity in oncology where it seems as if a new treatment that is more intense may actually cause fewer side effects. In the animal studies, FLASH radiation controlled the tumors approximately the same as conventional radiation therapy, but the incidence of side effects, morbidity, and mortality in the animal models were dramatically reduced.

We need to better understand the extent and basis for these early preclinical findings. However, we are committed to translating these findings into the clinic. Doing so can potentially reshape how we deliver radiation. These are very early days in this research, but these high-risk, high-reward opportunities may dramatically change the way we treat patients with cancer.

Engineering CAR T Cells to Influence Interferon Signaling

Another of the center’s research projects involves engineering CAR T cells to influence interferon signaling in a tumor. How will that process make CAR T cells more effective in patients with cancer? Might it make this therapy more effective in solid tumors?

As the research teams begin to understand how interferon signaling can both stimulate and inhibit the immune response against cancer, one important goal is to develop approaches to control which effect dominates. We believe that CAR T cells represent one such approach. For example, if we can understand how FLASH, or even conventional, radiation can positively influence an immune response, we might be able to “bottle up” this effect. The center, under the leadership of Carl June, MD (Director of the Center for Cellular Immunotherapies at the Perelman School of Medicine and Director of the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania), can then develop ways to engineer CAR T cells to deliver this effect to the tumor and improve tumor killing.

Alternatively, if we understand how the interferon pathway can promote immunotherapy resistance, we may be able to engineer CAR T cells to interfere with this unfavorable property. In theory, such a strategy not only could make CAR T cells intrinsically work better, but it may get other immune cells involved in attacking the tumor as well. We are hoping that the benefit of such strategies can be extended to solid tumors as well. ■

DISCLOSURE: Dr. Minn reported no conflicts of interest.

REFERENCES

1. Twyman-Saint VC, Rech AJ, Maity A, et al: Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373-377, 2015.

2. Formenti SC, Rudqvist NP, Golden E, et al: Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat Med 24:1845-1851, 2018.

3. Favaudon V, Caplier L, Monceau V, et al: Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice. Sci Transl Med 6:245ra93, 2014.

4. Durante M, Bräuer-Krisch E, Hill M, et al: Faster and safer? FLASH ultra-high dose rate in radiotherapy. Br J Radiol 91:20170628, 2018.


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