What Is Chemoimmunotherapy?

Chemoimmunotherapy means combining chemotherapy drugs with immunotherapy drugs to treat cancer. Yet, in addition to combining two therapies to attack a cancer in different ways, this combination may sometimes work better than would be expected if the benefits of the two therapies were simply added together (synergy).

As researchers learn more about the role of the immune system in cancer, as well as normal cells that surround a tumor (the tissue microenvironment), new ways to address even the most aggressive cancers are being designed.

Explore the rationale for combining chemotherapy and immunotherapy, examples of cancers for which this is currently being done, the potential risks and side effects, and what this may mean in the future.

Definition

To understand the potential benefits and risks of chemoimmunotherapy, it's helpful to look at the two types of treatments separately, and then see how they may work together to treat cancer.

Chemotherapy

Since the treatment is designed to kill off all rapidly dividing cells, side effects such as hair loss are common. Combining different chemotherapy drugs is already common practice (combination chemotherapy), and is thought to help address the fact that not all cells in a tumor are dividing at the same time.

While we often think of chemotherapy as simply killing cancer cells, some of these drugs may work in another way as well. It's been found that certain drugs such as Adriamycin (doxorubicin), Cytoxan (cyclophosphamide), and others not only kill cancer cells, but activate immune responses that can lead to further death of cancer cells (immunogenic cell death).

That our own immune systems have the capability of killing cancer cells is thought to underlie the uncommon phenomenon referred to as spontaneous remission of cancer (when a well-documented cancer simply disappears). This immune response is, in fact, the basis for the newer approach to cancer treatment called immunotherapy.

Immunotherapy

Many people wonder why our immune systems do not fight off cancer cells as they would, say, a bacteria. The immune system (for example, T cells), does have this ability, but cancers frequently find ways to hide from the immune system; either by disguising themselves as normal cells ("putting on a mask," so to speak) or by secreting substances that inhibit the immune system in the area of the tumor.

Immunotherapy works by "priming" the immune system so that it can do a better job of fighting cancer. Unfortunately, and though some people with advanced cancers have had dramatic responses to these drugs (durable responses), they currently work so well on only a minority of people with cancer.

With some tumors, it's thought that the cancer cells don't look abnormal enough to initiate a strong immune response. Often, however, there are pieces missing that would allow these drugs to work most effectively. For example, in order to mount an immune response to a cancer, the immune system needs to clearly "see" that cancer (antigens on the surface of the cells). This is where chemotherapy comes into the equation.

Rationale and Potential Mechanisms

Describing the potential benefits of chemoimmunotherapy requires reviewing some cancer biology. While this is challenging to understand, knowing the purpose of your treatment can sometimes be empowering in the journey. In the least, it can sometimes help people better cope with side effects, knowing that there is reasonable chance that a treatment will address the cancer.

There are a few different ways in which chemotherapy may enhance the effects of immunotherapy.

"Immunogenic Cell Death"

As noted above, in addition to directly killing cells (by halting cell division, etc), chemotherapy drugs may enhance the ability of the immune system to kill cancer cells. When cancer cells die, they not only get cleaned up by the immune system, but they activate the immune system. Not all death of cancer cells results in an activation of an immune response (immunogenic cell death).

When cancer cells die by certain methods (such as via some chemotherapy drugs and other treatments), they release chemicals (for example, some cytokines) that are important cancer fighters. This process also results in the recruitment and activation of natural killer cells (NK cells), cells that are active both in attacking tumors and enhancing surveillance for abnormal cells. From a different angle, chemotherapy may decrease the number of a type of cell in the immune system, regulatory T cells (Tregs), that can decrease the immune response.

Other methods being evaluated to make tumor cells more immunogenic include photodynamic therapy, radiation therapy, hydrostatic pressure, and oncolytic viruses.

Tumor Microenvironment

We tend to think of a cancer as a foreign lump of cells sitting alone in a region of the body, but this is far from the case. The tumor microenvironment, or the "normal" cells of the body that lie near a tumor, play a very important role in the growth and spread of cancers.

This effect can be either positive or negative. A negative effect might sound surprising, but we've learned that cancers don't function alone, and often find other "normal" cells to do some of their dirty work for them. Normal cells are recruited for many activities, such as helping cancers establish a blood supply (angiogenesis) in order to keep growing.

Challenges: Doses, Timing, and More

While it appears that chemotherapy has great potential to enhance the effectiveness of immunotherapy in some cases, the science is still young. When using chemotherapy, it's necessary to balance out the effects that the drugs have on both tumor cells and different immune cells via the dosage and schedule.

Chemotherapy Dosages

Conventionally, the approach with chemotherapy has been to use the maximum tolerated doses in an effort to kill off as many cancer cells as possible before resistance develops. Unfortunately, in very high doses, chemotherapy can result in suppression of the immune system (myelosuppression). Since activation of immune response is the goal of chemoimmunotherapy, very high doses could be counterproductive.

At the same time, too low a dose of chemotherapy may also be ineffective by failing to provide enough "evidence" (antigens) of tumor cells to stimulate the immune system appropriately.

For those who have concerns due to a low white blood cell count on chemotherapy (neutropenia), some degree of immune suppression may actually be good. Transient decreases in white blood cell count due to chemotherapy may help by sending the body a message that says "danger," that can lead to a greater release of chemical weapons (cytokines), activation of cancer-fighting T cells, and the recruitment of more immune cells into a tumor.

Research is in progress. This included approaches such as metronomic chemotherapy to see if these could enhance the immune response.

Timing

Timing of chemotherapy (how frequent), as well as when it is given relative to immunotherapy, is likely to also influence the effectiveness of chemoimmunotherapy.

There is some evidence that chemotherapy drugs may be more effective (at least in some cases) when T cells are already attacking a tumor (secondary to immunotherapy). This could also, in a sense, help to "clean up" cancer cells left over after the immune system does its job. In addition, it's thought that this timing may prevent the increase in immune suppressive cells (T regulatory cells, etc.) that often occurs after the immune system is stimulated by immunotherapy.

Further Enhancing Responses to Immunotherapy

In addition to chemotherapy, researchers are looking at other potential methods to make tumor cells more recognizable by the immune system (to increase their immunogenicity). Some of these include photodynamic therapy, radiation therapy, hydrostatic pressure, and oncolytic viruses.

Side Effects and Risks

The side effects of chemotherapy are well recognized and can include immunosupression, nausea, hair loss, and more.

The side effects of checkpoint inhibitors are frequently much different, and are easier to understand by looking at the mechanism behind these drugs. By stimulating the immune system, these drugs can tip the body in the direction of autoimmune disease to some degree. The most common symptoms are those that end in "itis" referring to inflammation, such as pneumonitis.

Fortunately, the combination of these two classes of drugs has been fairly well tolerated in several clinical trials to date.

Benefits and Examples

Chemoimmunotherapy is now being used—both via approved therapies and in clinical trials—for a number of different types of cancer. We will discuss only a few of these here, but it's likely that more trials will be developed in the near future for cancers that have not yet been approached with this combination.

Lung Cancer

The first combination of first-line chemotherapy and immunotherapy for non-small cell lung cancer (specifically lung adenocarcinoma) was approved in 2017. The trial leading to approval used a combination of the immunotherapy drug (a type of checkpoint inhibitor) Keytruda (pembrolizumab) with the two chemotherapy drugs Paraplatin (carboplatin) and Alimta (premetrexed), to show that the combination was both safe and more effective than chemotherapy alone.

Since that time, other combinations have been used and there are several clinical trials in place looking at the combination.

For people who are receiving immunotherapy either with or without chemotherapy, it's important to be aware of the phenomena of pseudoprogression. Unlike what is seen with chemotherapy, early responses to immunotherapy are not as dramatic (it takes more time to get the immune system working to fight cancer). Imaging tests (such as CT scans) can also look "worse" early on, even if a tumor is responding. When immune cells surround and infiltrate a tumor, it can make the tumor look larger on a scan, something referred to as pseudoprogression. Even though the tumor appears larger, it actually may be smaller.

Of interest, is that radiation therapy, particularly SBRT (stereotactic body radiotherapy) to treat metastases, has also been found to enhance the effectiveness of immunotherapy for some people. Via something that has been coined the "abscopal effect," radiation given to one area of the body may sometimes stimulate the immune system such that the treatment results in reduction of a tumor in a different region of the body away from the site of radiation.

Breast Cancer

Despite sometimes dramatic responses to immunotherapy with some solid tumors (such as lung cancer and melanoma), results of studies using immunotherapy in people with breast cancer have been disappointing. Unlike some tumors, breast cancers often have a "lower mutational burden," meaning that they look less abnormal to the immune system.

In one setting, however, combining immunotherapy with chemotherapy has been shown to be effective, specifically, with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1. A 2020 study compared the effectiveness of Keytruda (pembrolizumab) and chemotherapy (paclitaxel protein-bound, or paclitaxel, or gemcitabine plus carboplatin) to that of the chemotherapy drug alone. The overall median survival was 9.7 months for the group also given the immunotherapy drug (a checkpoint inhibitor) compared with 5.6 months in the group that received chemotherapy alone.

Research is in progress looking for ways to "wake up" the immune system in people who do not respond to immunotherapy, and some evidence suggests that chemotherapy may have a role in the future.

Lymphoma

Combinations of cancer treatments have long been used to treat different types of lymphoma, and in 2019 the first chemotherapy regimen for people with relapsed diffuse large B-cell lymphoma was approved. The drug, PolivyPolivy (polatuzumab vedotin-piiq), in combination with the chemotherapy drug Bendeka (bendamustine) and a rituximab medication further advanced the treatment of this challenging disease.

Other Cancers

Combinations of immunotherapy (checkpoint inhibitors as well as other types) and chemotherapy are being evaluated for many different types of cancer. As of June 2019, there were more than 170 clinical trials investigating checkpoint inhibitors and chemotherapy (chemoimmunotherapy) in different types of cancer.

Summary

The combination of immunotherapy and chemotherapy (chemoimmunotherapy) to treat cancer is an exciting advance in options for at least some people with cancer. These newer treatment approaches differ from those in the past (coined "slash, poison, burn" by some), and uses knowledge of the biology of cancer rather than trial and error as a basis.

This precision medicine, may not only lead to more effective treatments, but with fewer side effects. There are still many unanswered questions, but many clinical trials are currently in place that promise to bring more insight in the near future.