Abscopal Effect in Metastatic Cancer

The abscopal effect is a theory that describes why sometimes using local treatment to one area of a metastatic cancer (such as radiation therapy) may result in cancer shrinking in an untreated area. While this phenomenon was seen as a rare occurrence in the past, it has become more frequent with the arrival of immunotherapy drugs such as checkpoint inhibitors to treat cancer. The underlying mechanism for this phenomenon is still unclear, but it's thought that the localized treatment might prime the immune system to attack cancer cells in a distant region.

An abscopal response has been seen most commonly with metastatic melanoma, but has also been demonstrated in cancers such as non-small cell lung cancer, and kidney cancer, and it appears that the microenvironment surrounding tumors (the "normal" cells near a tumor) may play a role in whether the effect occurs or not.

There are many unanswered questions, but a large number of clinical trials are in progress looking for answers, as well as methods that might possibly enhance the abscopal effect.

Impact and Potential for Metastatic Cancer

Metastatic cancer, or cancer that has spread to regions beyond the original tumor (stage IV cancer), is notoriously difficult to treat.

While radiation has traditionally been used as a palliative treatment (to reduce symptoms but not extend life) or for local control of a cancer, an understanding of the abscopal effect, why it sometimes occurs, and methods to enhance the response may give physicians an additional method for treating metastatic disease. In other words, learning to enhance the abscopal effect could result in radiation becoming a standard part of treatment for (at least some) metastatic cancers.

Via the abscopal effect, radiation therapy may also potentially help people who did not previously respond to immunotherapy drugs begin to respond.

Abscopal Effect Basics

The abscopal effect can be better defined by looking at the root words of the term. Ab refers to "a position away from," and scopus means "target."

Local Versus Systemic Therapy

The significance of the abscopal effect is easier to understand by dividing cancer treatments into two main categories: local and systemic treatments.

Local treatments, such as surgery, radiation therapy, proton beam therapy, and radiofrequency ablation are most often used to treat early-stage cancers. These treatments are designed to eliminate cancer cells in a local area, usually the original location of a tumor.

Systemic treatments, or body-wide treatments, are usually the treatment of choice for metastatic (stage IV) solid cancers, as cancer cells have spread beyond the area of the original tumor. When this occurs, local therapy is unable to eliminate all of the cancer cells. Examples of systemic therapies include chemotherapy, targeted therapies, immunotherapy, and hormonal therapy. These treatments travel through the bloodstream to reach tumor cells wherever they happen to be in the body.

Local Therapy and Metastatic Cancer

Local therapies are sometimes used with metastatic cancer, but not usually with curative intent as it is with early-stage cancers. Radiation may help with symptoms, such as relieving bone pain from bone metastases or relieving an obstruction in the airways due to a large lung tumor.

Specialized radiation techniques such as stereotactic body radiotherapy (SBRT) are sometimes used for metastatic cancer with a curative intent when only a few metastases are present (oligometastases). For example, lung cancer that has spread to a single or only a few sites in the brain may be treated with SBRT (a high dose of radiation to a small area) in hopes of eradicating the metastases.

In these cases, it's thought that local therapy may somehow activate the immune system to fight cancer.

History

The abscopal effect was first hypothesized in 1953 by R. H. Mole, MD. At that time, it was called the "soluble effect" as it appeared that something about the treatment of one tumor influenced another tumor.

Following this description, the effect was rarely noted until the type of immunotherapy known as checkpoint inhibitors began to be used. Checkpoint inhibitors can be thought of as drugs that boost the immune system's ability to fight off cancer cells by "taking the brakes off" the immune system.

In 2004, animal studies gave further support to the theory. As checkpoint inhibitors entered the picture, a dramatic report published in 2012 in the New England Journal of Medicine found that radiation therapy combined with a checkpoint inhibitor resulted in the complete disappearance of distant metastases in a patient with metastatic melanoma. A more public example of the abscopal effect was presumably seen with former President Jimmy Carter's cancer.

The abscopal effect was demonstrated conclusively in a 2015 study using a different type of immunotherapy. A cytokine called granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with radiation therapy led to abscopal responses in people with non-small cell lung cancer and breast cancer.

Mechanism

The mechanism underlying the abscopal effect is still uncertain, though researchers believe an underlying immune response dependent on the microenvironment (normal cells surrounding the tumor) plays a significant role.

Immune Actions

Our immune systems know how to fight cancer but, unfortunately, many cancers have found a way to either hide from the immune system (like putting on a mask) or secrete substances that suppress the immune system.

One hypothesis (simplistically) is that the local death of cells releases antigens⁠—proteins on cancer cells that the immune system can recognize as abnormal or "not-self". These are detected by cells in the immune system that present the antigens to other immune cells, resulting in the priming of cytotoxic T cells that can then travel around the body to attack tumor cells in other regions. This recognition of antigens by the immune system, so an immune response can be mounted, is similar to what happens when people receive immunizations against bacteria and viruses.

Tumor Microenvironment

Since our immune systems are designed to recognize and eliminate cancer cells, many people wonder why all cancers are not simply destroyed by the immune system. As noted, many cancer cells have figured out ways to hide from the immune system or secrete chemicals that suppress the immune system, and to understand this better it's helpful to look at the tumor microenvironment, or what's happening with normal cells that surround a tumor.

Cancer cells are not simply a clone of cells that grows in a chaotic way by themselves, but they've found ways to control healthy, normal cells in their vicinity.

Immune Suppression/Immune Tolerance of the Microenvironment

The microenvironment around tumors is frequently immunosuppressed. This means that unique proteins on cancer cells (antigens) would not be seen (detected) by the immune system. Since they are not seen, they can't be presented to cytotoxic T cells so that these cells can't be trained to go out and hunt and kill cancer cells.

The immunotherapy drugs that many people are now familiar with—checkpoint inhibitors—may work (at least in one way) by improving the immune function of the tumor microenvironment. In studies, these primed T cells have been demonstrated when the abscopal effect is seen.

Radiation therapy not only kills cancer cells but may alter the tumor microenvironment as well.

Tissue Heterogenicity

We know that cancers aren't a single clone of abnormal cells. Cancer cells continue to evolve and develop new mutations, and different parts of a tumor may actually appear quite different on a molecular level or even under the microscope. By priming the immune system, radiation may help T cells recognize more aspects of the cancer, or heterogeneity, making cancer more visible to the immune system.

Cancer Types and Patient Characteristics

Evidence of the abscopal effect with the combination of radiation therapy and immunotherapy drugs is becoming more common, but is still far from universal and varies significantly between different types of cancer, different people, and different treatments.

Defining the Abscopal Effect for Study Purposes

In order to be consistent when looking at studies (at least since 2015), the abscopal effect is defined as a reduction of an area of a distant tumor by at least 30% when local treatment is given. An abscopal response can either be partial (30% or greater reduction in tumors distant to the site of radiation) or complete (leading to no evidence of disease or NED).

Types of Cancer

The abscopal effect has now been seen with a number of cancer types, with the greatest incidence being with metastatic melanoma. Given the potential to have another method for addressing metastatic cancer, researchers have been trying to figure out what predicts whether cancer will respond or not.

Tumor-infiltrating cells (lymphocytes that move from the bloodstream into a tumor) can have functions that are either pro-tumor or anti-tumor depending on the predominant cell type. Regulatory T cells (a special type of CD4+ T cells) and macrophages appear to have pro-tumor functions, whereas CD8+ T cells have anti-tumor effects. Tumors that are infiltrated by CD8+ T cells are more likely to exhibit the abscopal effect.

Cancers that have significant T cell infiltration include lung adenocarcinoma, renal cell carcinoma (kidney cancer), and melanoma. Other cancers on this list include:

• Squamous cell cancers of the head and neck
• Cervical cancer
• Colorectal cancer
• Thymic cancer
• Squamous cell carcinoma of the lungs

At least until the abscopal response is better understood and ways are developed to enhance the response, these are the cancers in which the effect is most likely to be seen. That said, and as noted in the conclusive 2015 study above, cancers that do not have significant T cell infiltration such as breast cancer have shown the response.

Patient Characteristics

There are also patient characteristics that may indicate who is more likely to have an abscopal response. One of these is the presence of a healthy immune system. People who have bone marrow suppression due to chemotherapy, or have cancers that have infiltrated the bone marrow, are less likely to have the response.

Tumor Burden

Tumor burden is a term physicians use to describe the extent of cancer in the body. A larger tumor burden may be related to a greater volume of tumor, greater tumor diameter, a greater number of metastases, or a combination of these.

At least in studies thus far, it appears that people who have a greater tumor burden are less likely to have an abscopal response to radiation plus immunotherapy.

Cancer Treatments Associated with Abscopal Response

The abscopal effect is seen by far most commonly when immunotherapy drugs are combined with radiation therapy, though case reports have been published when radiation is used alone, and with cryotherapy (in men with prostate cancer). It's thought that using chemotherapy combined with immunotherapy may have a somewhat similar effect.

Types of Immunotherapy and the Abscopal Effect

There are many different types of immunotherapy, with the different forms using either the immune system or principles of the immune system to fight cancer.

Of these, checkpoint inhibitors have been evaluated most widely with respect to the abscopal effect. These drugs work, in essence, by taking the brakes off of the immune system so it attacks cancer cells.

Checkpoint inhibitors currently approved (with different indications) include:

• Opdivo (nivolumab)
• Keytruda (pembrolizumab)
• Yervoy (ipillimumab)
• Tecentriq (atezolizumab)
• Imfinizi (durvalumab)
• Bavencio (avelumab)
• Libtayo (cemiplimab)

(Most of these drugs are PD1 or PD-L1 inhibitors, with Yervoy being a CTLA-4 inhibitor.)

Other forms of immunotherapy that are being looked at for the potential of harnessing the abscopal effect include additional checkpoint inhibitors, CAR T-cell therapy (a type of adoptive cell therapy), immune system modulators (cytokines), and cancer vaccines.

Types of Radiation and the Abscopal Effect

The abscopal effect has been seen most commonly with conventional external beam radiation therapy, but is also being evaluated with stereotactic body radiotherapy, proton beam therapy, and other local treatments such as radiofrequency ablation.

External Beam Radiation Therapy

A 2018 review of 16 clinical trials looking at people with metastatic melanoma who received the checkpoint inhibitor Yervoy (ipilimumab) plus radiation therapy found a significant number of abscopal response rates and improved survival (without any significant increase in side effects). The abscopal effect was noted in a median of 26.5% of people on the combination of Yervoy and radiation, with adverse events no greater than people in control groups who received Yervoy alone.

With lung cancer, a 2017 study in Lancet Oncology (KEYNOTE-001) found that people with advanced non-small cell lung cancer who had previously been treated with any radiation had a significantly longer progression-free survival and improved overall survival when treated with Keytruda (pembrolizumab). With radiation to any site, the overall survival was 10.7 months versus 5.3 months without radiation.

There are several case reports of the abscopal effect in non-small cell lung cancer, with some patients showing no evidence of disease for an extended period of time following the combination of radiation therapy and checkpoint inhibitors.

Rare case reports have also noted the abscopal effect with radiation in at least one person with cancers such as breast cancer, esophageal cancer, liver cancer, and prostate cancer (with cryotherapy).

With Stereotactic Body Radiotherapy

The abscopal effect has also been demonstrated with localized, high dose radiation in the form of stereotactic body radiotherapy (SBRT). In a 2018 study published in the Journal of Clinical Oncology, people with advanced non-small cell lung cancer were assigned to one of two groups. One group received Keytruda (pembrolizumab) alone, while the other received Keytruda in combination with SBRT to one site of metastasis within seven days of beginning the Keytruda. The response rate of those who received the combination was 41%, in comparison to only 19% in those who received Keytruda alone.

Similarly, a 2018 study looking at the combination of immunotherapy with SBRT versus immunotherapy alone for people with melanoma with brain metastases found that the combination was associated with nearly double the overall survival.

Radiation Characteristics and Likelihood of the Abscopal Effect

The optimal dose, fractionation, timing, and field size of radiation is still unknown, but responses related to SBRT suggest that a small radiation field has been effective in eliciting a response, at least for some people. Since T cells are very sensitive to radiation, treatment to a larger area or a longer regimen of radiation may lower the chance that the abscopal effect will be seen.

Potential to Improve Response to Immunotherapy

An exciting potential use of the abscopal effect may be in people who do not initially respond to immunotherapy drugs (checkpoint inhibitors). While these drugs can sometimes be very effective in shrinking tumors such as melanoma or non-small cell lung cancer, and sometimes even result in complete remission, they only work in a relatively small percentage of people.

In particular, tumors that have low PD-L1 levels or a low mutational burden tend to not respond well to these drugs. There are also some types of tumors that don't respond well to checkpoint inhibitors at all.

The hope is that radiation may lead to these drugs working in some people for which they were previously ineffective. A 2018 study published in Nature Medicine looked at people with metastatic non-small cell lung cancer who did not respond to Yervoy (ipilimumab) alone compared to people treated with a combination of Yervoy and radiation. Among those receiving the combination treatment, 18% of those enrolled and 33% of people who could be adequately evaluated had an objective response to treatment. Overall, the combination of the checkpoint inhibitor plus radiation resulted in disease control in 31% of the people. Of those who achieved disease control, the overall survival was 20.4 months compared with 3.5 months in the control group.

Immune cells were analyzed in both those who did not respond and those who responded (in whom radiation induced a response to Yervoy) to help determine the mechanism that led to the abscopal response. Current biomarkers used to predict a response to checkpoint inhibitors—PD-L1 expression and tumor mutational burden—did not predict whether a person would respond.

Instead, the induction of interferon-beta and the increase and decrease of distinct T cell receptor clones predicted a response, suggesting that radiation may be immunogenic (result in an immune response to tumor in other regions).

Limitations and Side Effects

At the current time, the abscopal response is noted only in a small percentage of people receiving a combination of checkpoint inhibitors and radiation therapy, and many questions remain. Some of these unknowns include:

• The optimal dose, fractionation, and duration of radiation (studies to date looking at animal models have been conflicting)
• The optimal field size of radiation (a smaller field size may be better as T cells are sensitive to radiation)
• The timing of radiation relative to immunotherapy whether before, during, or after. (In the study with metastatic melanoma, using Yervoy at the same time as radiation was effective, but other studies suggest different timing may be preferable and this may also vary with the particular immunotherapy drug.)
• Whether radiation to some regions (for example the brain vs. the liver) is more likely to result in an abscopal response than others

Many clinical trials are in progress (well over one hundred) looking to answer some of these questions. In addition, studies are looking at the tumor microenvironment in hopes of further understanding the biology behind the abscopal response to enhance the chances it will occur.

Side Effects

It's important to look not only at the effectiveness of treatments but the incidence of side effects and adverse reactions when combining radiation with immunotherapy for metastatic cancer. As with any treatment, there are side effects of radiation therapy that may occur.

In studies thus far, the combination of radiation and immunotherapy drugs is usually well tolerated, with toxicities similar to those seen on immunotherapy drugs alone.

Role in Cancer Treatment Today

There's currently debate over whether radiation therapy should ever be used primarily in hope of eliciting the abscopal effect, and most physicians believe radiation in combination with immunotherapy drugs should be reserved for those who could benefit from radiation.

This is particularly true as there are many unanswered questions. It's fortunate, however, that research on the abscopal effect is expanding at the same time as researchers are studying the benefits of treatment of oligometastases, and whether treating solitary or only a few metastases from a solid tumor to another region can improve outcomes.

The Future: Research and Potential Impact

There is much to be learned about harnessing the abscopal effect, and early research offers hope for additional uses of this phenomenon in the future.

Since the combination of radiation and immunotherapy can work essentially as a vaccine (teaching our immune systems to recognize cancer cells by "seeing" cancer cells killed by radiation), the effect may be helpful in creating anti-tumor vaccines in the future. There is even hope that increasing anti-cancer immunity in this way may someday play a role not only in metastatic cancers, but also in early-stage cancers before progression and metastases occur.

Evaluating the abscopal effect and the role of the tumor microenvironment is also helping researchers better understand the underlying biology of cancer growth and progression, and may give rise to further therapies in the future.

A Word From Verywell

There is much to be learned about the abscopal effect when combining local effects such as radiation therapy with immunotherapy drugs, including the mechanism by which this sometimes occurs. It's hoped that further research will lead to ways to increase the chance the abscopal effect will occur in a larger number of people. Since cancer metastases are responsible for 90% of cancer deaths, research that specifically addresses metastases is critical to reducing deaths from cancer.