In 2012, 6-year-old Emily Whitehead’s acute lymphoblastic leukemia returned, and no traditional treatment options remained. So she became the first child to receive CAR-T immunotherapy, which engineered her T cells to fight the cancer. More than a decade later, Emily is cancer-free. Her success spawned new hope that immunotherapy could change cancer care, beating previously untreatable cancers.

In reality, today’s CAR-T immunotherapies only help a small number of patients with certain cancers. Nonetheless, scientists remain optimistic about expanding the range of cancer treatments that make use of a patient’s immune system.

Wenbin Lin
Wenbin Lin, PhD
James Franck Professor of Chemistry, University of Chicago

Beyond CAR-T therapy, immune checkpoint inhibitors raised more hope in the oncology community. Work in this field even earned James Allison, PhD, of the University of Texas MD Anderson Cancer Center and Takuku Honjo, MD, PhD, of Kyoto University in Japan the Nobel Prize in Physiology or Medicine 2018. In normal situations, immune checkpoints prevent T cells from attacking healthy cells. When T cells bind cancer cells, though, checkpoints can slow down the immune attack, putting the brakes on the immune system. Immune checkpoint inhibitors release the brakes, letting the T cells get back to work fighting the cancer. Like CAR-T therapy, though, current immune checkpoint inhibitors only work in a limited number of patients.

As Mark Smyth of the University of Queensland in Australia and his colleagues put it: “Many patients have innate or acquired resistance to immunotherapies.”1 Adding even more complexity to the challenge of using immunotherapy, Wenbin Lin, PhD, the James Franck Professor of Chemistry at the University of Chicago, says there is as yet no strategy to identify in advance patients who will respond to it. These are some of the hurdles that scientists around the world confront in the modern war on cancer.

Taking a tumor’s “temperature”

When asked about today’s challenges in using immunotherapy, Lei Zheng, MD, PhD, professor of oncology at Johns Hopkins School of Medicine, points out that the “tumor microenvironment is extremely heterogeneous.”

Lei Zheng
Lei Zheng, MD, PhD
professor of oncology
Johns Hopkins School of Medicine

Broadly, tumors exist in two categories: hot or cold. “We consider a hot tumor to be more immunogenic, and they tend to respond to immunotherapy,” Zheng explains. “Immune cells do not enter cold tumors—sometimes called the immune desert.” In a very general way, this distinction between tumors explains why immunotherapy works for some patients but not others. “For cold tumors, as a very first step, we would need to convert their microenvironment into a ‘hot’ one,” Zheng says.2

Cold tumors are one aspect of resistance to immunotherapy, but that’s not the end of it. “Even if a patient responds very well to immunotherapy and goes into remission, the cancer eventually evolves resistance to the therapy in the majority of patients,” Zheng says.

cold and hot tumor
A cold tumor (left) includes fewer targets of checkpoint inhibitors, such as PD-L1 (green), than does a hot tumor (right).

Reviving T cells

Even activated T cells can become exhausted and stop fighting cancer. As explained by Andrew Chow, MD, PhD, a thoracic oncologist at the Memorial Sloan Kettering Cancer Center, and his colleagues: “Cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity.”3

At the start of T-cell exhaustion, immune checkpoint inhibitors can revive the struggling cells. Eventually, though, T cells become terminally exhausted, or so scientists thought.

Amanda Poholek, PhD, assistant professor of pediatrics and immunology at the University of Pittsburgh’s School of Medicine, and her colleagues explored the cause of T-cell exhaustion. Part of it arises from changes in the chromatin—the DNA-protein complex in chromosomes—of the CD8+ T cells that can invade tumors. As Poholek and her colleagues reported: “We found that terminally exhausted T cells had unexpected chromatin features that limit their transcriptional potential.”4 In addition, the scientists found that the low level of oxygen in tumors contributes to T-cell exhaustion.

Nonetheless, Poholek’s team found that even exhausted T cells can be stimulated to increase gene expression. That’s one potential way to revive these cells. In addition, the scientists showed that T cells can be engineered to resist the effects of a tumor’s low-oxygen environment.

Future immunotherapies could make use of these findings. As a result, T cells might be engineered or stimulated to attack more cancers and for longer.

Creating combinations

Some cancers resist most traditional treatments, as well as immunotherapy. One of those is pancreatic cancer, especially once it spreads. According to Cancer Research UK, only 10% of patients whose pancreatic cancer is metastatic at the time of diagnosis survive for a year.5

In 2018, Robert Vonderheide, MD, PhD, director of the Abramson Cancer Center at the University of Pennsylvania’s Perelman School of Medicine, and his colleagues explained: “A key component of pancreatic cancer’s lethality is its acquired immune privilege, which is driven by an immunosuppressive microenvironment, poor T cell infiltration, and a low mutational burden.”6 They also noted that immunotherapies failed at that time in treating pancreatic cancer, but the scientists expressed optimism that combinations of therapies might produce better outcomes.

Vonderheide and his colleagues might have been right. Recently, Ronald DePinho, MD, professor of cancer biology at the University of Texas MD Anderson Cancer Center, and his colleagues showed that T-cell based immunotherapy aimed at three targets extended the survival time of mice with pancreatic cancer by 90%.7

Gastric cancer poses another nearly unmanageable challenge for oncologists. According to a team of scientists from the Fourth Hospital of Hebei Medical University in Shijiazhuang, China, and the University of Pennsylvania: “The clinical efficacy of conventional therapies is limited, and the median overall survival … for advanced-stage gastric cancer is only about 8 months.”8 Nonetheless, the scientists added that “immunotherapy has become an effective treatment modality after surgery, chemotherapy, radiotherapy, and targeted therapy.”

As these studies showed, combinations of various forms of immunotherapy, as well as combining traditional treatments and immunotherapy, could extend the applications of these treatments and improve the results.

Getting to the source

Much of cancer’s resistance to immunotherapy takes place in the tumor microenvironment (TME), which consists of the noncancerous cells that surround the cancerous ones. The TME is a difficult battleground. As Vasso Apostolopoulos, PhD, Vice Chancellors Distinguished Professorial Fellow at Victoria University in Melbourne, Australia, and her colleagues put it: “A developing TME is a complicated, dynamic entity.”9

Moreover, Apostolopoulos and her colleagues added: “Determining the relationship between tumor cells and the TME is crucial to developing cancer treatments.” Unraveling that relationship, though, is not easy.

Chemokines make up one family of proteins in the TME that can slow down or speed up cancer growth. Ordinarily, chemokines aid in the killing of cancer cells, but cancer cells can also turn chemokines into tumor helpers that prevent the infiltration and activation of immune cells in the TME. Consequently, Sebastian Kobold, MD, PhD, professor of medicine and experimental immuno-oncology at the Ludwig-Maximilians-Universität München in Germany, and his colleagues noted: “Chemokines may represent valuable prognostic biomarkers of response to immunotherapy and a strategy to improve immunotherapies.”10 Kobold’s teams suggested two possible chemokine-based improvements. Existing therapies might be combined with antitumor chemokines, or CAR-T cells could be engineered to make more antitumor chemokines.

Although much of immunotherapy involves T cells, other immune cells could be engineered to kill cancer. One example is macrophages, which can even infiltrate cold tumors. For instance, Heinz Läubli, MD, PhD, group leader in the cancer immunotherapy laboratory at the University of Basel in Switzerland, and his colleagues explained that CAR-modified macrophages (CAR-Ms) “have demonstrated antigen-specific tumor phagocytosis, induce a proinflammatory TME, and boost antitumor T cell activity in humanized mouse models.”11

Developing new delivery methods

No matter how much scientists learn about the TME or how many new biotherapeutics they develop, the treatment needs to reach the right targets. Nanoparticles offer one way to do that.12

“You can take advantage of the nanoparticle’s intrinsic tendency to localize in a tumor,” says Lin. Plus, scientists can load a nanoparticle with an anticancer cocktail.

One place that nanoparticle-based therapies might work is in non-small cell lung cancer (NSCLC). Although some NSCLC patients respond to checkpoint inhibitors, most do not. Wassana Yantasee, PhD, CEO of PDX Pharmaceuticals, and her colleagues packed nanoparticles with an inhibitor of PLK1, which is overexpressed in many cancers, and a checkpoint inhibitor. The combination, the authors reported, “significantly reduces tumor progression in mice compared to each drug alone.”13

Other molecules, such as mRNA, can also be delivered in nanoparticle-based immunotherapies. As one example, mRNA can be used to impact signaling pathways in ways that cause immune-system cells to inhibit the growth of cancerous cells. Just as in the development of mRNA­based vaccines against SARS-CoV-2, immunotherapy applications of mRNA must deal with the fact that naked mRNA is unstable and not taken up well by cells. Loading the mRNA in nanoparticles can overcome those issues. Various forms of nanoparticles, including lipid and polymeric ones, have been tested. Nonetheless, Yizhou Dong, PhD, professor of oncological sciences at the Icahn School of Medicine at Mount Sinai, and his colleagues noted: “Despite the significant progress, mRNA-based cancer immunotherapy is still in its early stage and thus more investigations are needed to elaborate pharmacokinetic profiles, improve the efficacy, and minimize toxicity.”14

For any form of immunotherapy—and for that matter, cancer treatment in general—getting the drug to its target poses a difficult challenge. Instead of using intravenous delivery, scientists would like to get the immunotherapy directly to the cancer. Nanoparticles help with that targeting, but it could potentially be accomplished in other ways, such as with a hydrogel placed at the location of the cancer. Some scientists think this might work. “By analyzing the results of many pre-clinical hydrogel-enabled immunotherapy studies, we describe that local hydrogel delivery is a promising approach to increase the efficacy and decrease systemic toxicities of immunotherapies,” wrote Patrick S. Doyle, PhD, the Robert T. Haslam (1911) Professor of Chemical Engineering at the  Massachusetts Institute of Technology, and his colleagues.15 Nevertheless, these scientists added: “Despite the many pre-clinical successes of hydrogels for the delivery of immunotherapies for treatment of cancer, hydrogels still face challenges in getting to the clinic and eventually approved.”

Could behavior impact efficacy?

Although most of today’s work in immunotherapy focuses on biomolecules and blockers, immune-system cells and disease resistance, other aspects of biology might also impact the efficacy of these treatments.

Chiara Jongerius
Chiara Jongerius, PhD
postdoctoral researcher
Amsterdam University Medical Centers

“Behavioral factors, such as stress, exercise and classical pharmacological conditioning, predict cancer incidence, recurrence and the efficacy of conventional cancer treatments,” according to a review by Chiara Jongerius, PhD, a postdoctoral researcher at Amsterdam University Medical Centers, and her colleagues.16 “Given the important role of the immune system in these processes, certain behavior may be promising to complement immune checkpoint inhibition therapy.”

Still, this is only an emerging field. When asked what is known about how a patient’s behavior might impact the efficacy of immunotherapy, Jongerius says, “Not much so far.” She added, “We’re now starting to look at this mostly preclinically, not so much in patients.”

Jongerius is primarily looking at the potential impact of exercise and stress. “We let mice run voluntarily on a treadmill—run as much as they want—and then we look at the effects on tumor growth and on the immunotherapy, almost exclusively checkpoint inhibitors.” So far, she can’t say much about the results, because they have not been published. Still, she notes: “There is a large window of opportunity if you look at this therapy and how we can improve it, and we hope that behavior is one of these ways to improve the efficacy of immunotherapy in patients over the long run, but for now, this is all very hypothesis generating.”

Behavioral Factors to Modulate Immunotherapy Efficacy in Cancer illustration
In Behavioral Factors to Modulate Immunotherapy Efficacy in Cancer, Chiara Jongerius and her colleagues depicted the potential impact of behavioral modifications—stress modulation, exercise, and traditional drugs—on the effectiveness of immunotherapy. (Image created with

For the moment, no scientist knows the breadth of research that might improve the efficacy of immunotherapy and make it useful in more patients with different forms of cancer. What scientists do know is that learning more about cancer’s defensive mechanisms and how immunotherapy can be modified to overcome these defenses promises better immunotherapies in the future. For Emily Whitehead and many others, even some of the first immunotherapies proved to be life-saving, and many more improvements surely lie ahead.



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Mike May is a freelance writer and editor with more than 30 years of experience. He earned an MS in biological engineering from the University of Connecticut and a PhD in neurobiology and behavior from Cornell University. He worked as an associate editor at American Scientist, and he is the author of more than 1,000 articles for clients that include GEN, Nature, Science, Scientific American, and many others. In addition, he served as the editorial director of many publications, including several Nature Outlooks and Scientific American Worldview.

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