3-D rendering of a t-cell lymphocyte with receptors for cancer cell immunotherapy.

Cancer is the ultimate betrayal of one’s body. The disease is marked by a group of cells showing abnormal growth and division, upsetting the careful balance of the human body. These cells grow, pushing out the normal cells, and spread, until the body is unable to handle the deluge any longer. 

The standard course of treatment for most cancers includes surgery, radiation therapy and/or chemotherapy. However, some patients do not respond to these treatments, especially those in the advanced stages of cancer. So what can be done for these patients?

One option is to use a patient’s own immune system—the very thing that turned on the body in the first place—to attack and kill the disease. This is called immunotherapy, and it’s one of the most innovative and promising approaches to cancer treatment today. 

In 2016 alone, the FDA approved immunotherapies for advanced forms of lung, kidney, bladder and head and neck cancers, as well as Hodgkin lymphoma. In recognition of immunotherapy’s ability to extend and improve the lives of patients with little to no treatment options, the American Society of Clinical Oncology (ASCO) named the treatment the Advance of the Year for 2016.

“Although it has conceptually been in development over a century, cancer immunotherapy in the last couple of years has really revolutionized treatment options for several patients who had previously untreatable cancers, and it has also been a paradigm shift in clinical oncology as what may become the mainstay of cancer treatment,” Dr. Duane Mitchell, MD, director of the University of Florida Brain Tumor Immunotherapy Program, told Laboratory Equipment. “At least in some patients, [immunotherapy] can be the primary intervention for treating cancer, and perhaps the most potential for a curative treatment.”


Mitchell’s program is only four years old, but has already developed several approaches to immunologic treatment for both pediatric and adult brain tumor patients. He himself has served as principal investigator on seven first-in-human protocols through FDA-approved clinical trials.

While there are multiple promising avenues in immunotherapy, Mitchell’s team at UF focuses on adoptive T-cell therapy, or adoptive cellular therapy. This is a personalized approach in which a patient’s own immune cells are harvested from their blood and altered to have specific proteins, called receptors. These receptors allow T-cells to recognize tumor cells as foreign invaders. The changed T-cells are grown in large numbers in the lab before being returned to the patient’s body. Once there, the trained T-cells seek out and destroy cancer cells. 

“Although a very complex and personalized treatment modality, we’ve seen that this can be a really potent, effective and specific means at amplifying the body’s ability to fight invasive tumor cells,” Mitchell said. 

Using this approach, Mitchell has one ongoing clinical trial in pediatric patients with recurrent brain tumors that have failed traditional therapy, like radiation and chemo. The lab is also in the process of opening three additional clinical trials, both in pediatric and adult patients with different types of brain cancers. In early-phase trials, there were preliminary signs of effectiveness.

But, brain malignancies are among the hardest types of cancers to treat—making immunotherapy in this area even more critical. 

One thing that makes brain malignancies unique with respect to other cancers is locale. Since it’s such a vital organ, the brain is hardwired to keep potentially toxic substances out via the blood-brain barrier, a membrane barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system. If the blood-brain barrier is functioning correctly, it is also keeping out the chemicals, drugs, chemo and other substances used to treat brain cancer. According to Mitchell, it’s estimated that as little as 2 percent of the drugs developed for treating cancers can reach appreciable concentrations in the brain. However, a patient’s own, albeit altered, immune cells have a clear, unblocked pathway to the brain. 

“A second challenge is these tumors are very heterogeneous,” Mitchell explained. “Even in a given patient, the tumor cells display a variety of changes, which means treatments that may be effective at eradicating 99 percent of the brain tumor cells can still select a small population of cells that are resistant and grow back. Now, the new population of cells is completely resistant because it was selected out from a very heterogeneous mixture of tumor cells.”

However, Mitchell says a number of recent developments are working to make the brain more accessible to drugs, including a laser-based advancement at his own center at the University of Florida. 

Researchers have discovered the blood-brain barrier opens soon after a procedure known as MRI-guided laser ablation, in which physicians use a probe no larger than a pencil to heat and kill tumors. UF’s chief of neuro-oncology, David Tran, found an unexpected, beneficial side effect: the laser beam creates the perfect temperature around the tumor—just warm enough to disrupt the blood-brain barrier but not so hot that neurons die.

In a pilot trial, 14 brain tumor patients underwent laser ablation and were treated with doxorubicin, a chemotherapy drug that is normally blocked by the blood-brain barrier. Preliminary data suggest there could be a survival benefit to giving chemotherapy during the four- to six-week opening in the blood-brain barrier.

PD-1 checkpoint inhibitors (blue) are rapidly gaining FDA approval. PDL-1 (red) is a protein oft targeted in cancer research, as it is suspected to play a major role in suppressing the immune system.

Checkpoint inhibitors

While T-cells look extremely promising and are making their way through clinical trials, it was a different approach that prompted ASCO to name immunotherapy the advance of the year. 

Blocking immune checkpoints has been particularly effective against a range of different cancers. Immune checkpoints are specialized proteins that act as brakes on the immune system, ensuring immune defenses are engaged only when they are needed and for as long as they are needed. They prevent the immune system from becoming overactive. Thus, cancer treatments known as immune checkpoint inhibitors unleash the immune system to attack cancer. 

Since the first reports of immune checkpoint inhibitors shrinking advanced melanoma in 2011, research in this area has taken off at an incredible pace—establishing immunotherapy as a mainstay cancer treatment. 

Atezolizumab was among the record-setting number of immunotherapy treatments approved last year for a variety of cancers. It was also the first PD-1 checkpoint inhibitor to gain FDA approval for any use. PDL-1 is a protein oft targeted in cancer research, as it is suspected to play a major role in suppressing the immune system, allowing cancer cells to evade and spread. 

Specifically, atezolizumab has been life-changing for patients with advanced bladder cancer. Prior to atezolizumab’s approval, the standard of care for bladder cancer was cytotoxic chemotherapy, which has a response rate of 10 percent and survival of four to six months in a frail patient population. 

The approval of atezolizumab was based on an early clinical trial of patients with previously treated metastatic urothelial cancer, the most common type of bladder cancer. It is also for patients whose cancer continues to grow after platinum-based chemo. 

“This was a huge breakthrough to have a new treatment option for patients. It’s based on a lot of work looking at the role of the immune system in cancer, and the fact that several lines of evidence led to testing immunotherapy in bladder cancer, including that [it] has a very high mutation load,” said Dr. Jonathan Rosenberg, MD, the author of the single-arm study that lead to the FDA’s accelerated approval of atezolizumab. Rosenberg is affiliated with Memorial Sloan Kettering Cancer Center in New York. 

So far this year, the FDA approved the drug nivolumab, for those with bladder cancer who have failed prior chemotherapy, as well as the PD-1 inhibitor pembrolizumab. That approval was based on Phase-3 data of a randomized trial that showed patients who received pembrolizumab lived significantly longer than those who received chemotherapy, and with fewer side effects. 

After atezolizumab’s approval for bladder cancer, it was tested in other types of cancer as well. While some of those tests are still ongoing, it was recently approved by the FDA for patients with previously treated, metastatic non-small-cell lung cancer (NSCLC). The approval was based on two large clinical trials that showed patients who received atezolizumab lived longer (14 and 13 months) than those who received docetaxel chemotherapy (9 months). 

But it appears atezolizumab is not the only PD-1 inhibitor that is successful across cancers. 

A similar clinical trial of pembrolizumab for non-small-cell lung cancer—which accounts for the majority of lung cancers (85 percent)—found the drug extended survival two months longer than the standard docetaxel chemotherapy. Specifically, in the group of patients with higher levels of PD-L1, the median survival with pembrolizumab was even longer—15 months versus 8 months.

“These findings established pembrolizumab as a new standard option for patients with previously treated, advanced NSCLC,” the ASCO report reads. “The study also sparked a national conversation about the importance of PD-L1 biomarker testing to select patients who are most likely to benefit from immune checkpoint inhibitors.”

Biomarkers play a crucial role in patient selection for immunotherapy, but they still don’t explain why immune checkpoint inhibitors work so well in some cancers and not at all in others. For example, researchers believe cancers with high levels of PD-L1 will respond well to PD-1 checkpoint inhibitors, and those without PD-L1 will not benefit at all. However, several clinical trials have shown this is not always the case, with some cancers that have low levels of PD-L1 unexpectantly responding to PD-1 inhibitors.

“The challenge is right now we have a simplistic, binary biomarker for selecting patients—and cancer is not a simplistic disease,” Dr. Lynette Sholl, MD, a pathologist at Brigham and Women’s Hospital told Laboratory Equipment. “It’s not all about PDL-1, which is the only biomarker we have to rely on in clinical practice right now. It just doesn’t tell the full story.

“But a lot of the genetic biomarkers [are present] in fairly small numbers of people,” Sholl continued. “Putting together big randomized control trials is very challenging. A lot of the data we’re looking at for these individual biomarkers is retrospective and multi-institutional.”

ASCO believes there is a simpler albeit just as important challenge to solve before biomarker research can continue.

“A major issue is the lack of standardization of PD-1 and PD-L1 analyses,” reads the cancer organization’s report. “It is unclear which assay or reagent is optimal or whether expression in only the cancer cells or in cancer cells plus surrounding stromal and/or immune cells should be counted. Furthermore, even using one assay and one method of analysis, cutoffs have varied. These issues need to be resolved before this marker can be considered sufficiently robust for clinical decisions.”

That being said, researchers in the field already see progress toward better genetic understanding of cancers and tumors. Current studies are focusing on not just the biology of the tumor cells, for example, but also on the biology of the immune system and the immune microenvironment within tumor cells.

“We’re gaining a better understanding of some of the characteristics that make these tumors likely to respond to certain treatments and less likely to responds to others,” Mitchell said. “It’s already having an impact on how we think about combining treatments and testing treatment approaches in clinical trials. I think we’ll see a significant increase in the efficiency as well as the efficacy in the approaches that we evaluate going forward.”

Combination therapy is perhaps the hottest topic within immunotherapy circles, today. Researchers are actively investigating the potential of immunotherapy coupled to standard treatments like radiation and chemotherapy, since those continue to work in some patients. Other researchers are exploring the benefits of combining two or more immunotherapies, while still others are looking at how new technologies can be coupled with immunotherapy to make it even stronger. 

For example, UF’s Tran is exploring how his laser ablation technology described earlier can be combined with a PD-1 inhibitor. Early results suggest the laser technology can indeed enable the body’s immune system to precisely attack a foreign tumor.

“In the very near future, I think we may see the idea of engaging your immune system to battle cancer as one of the more common approaches we are using,” said Mitchell. “Just like today we think of surgery, radiation and chemotherapy as the standard of treatment. I think we’re going to see immunotherapy become the mainstay of treatment, and the question will be ‘how do we now most effectively utilize and combine immunotherapy with chemo or radiation or other new, more specific targeted therapeutics?’ This is going to be a field that will continue to grow and have major impact on diseases that we call incurable today, and I think we will be having a different conversation about many of these cancers in the not too distant future.”

Film MRI of a brain tumor. Brain malignancies are among the hardest cancers to treat due to their location in the human body.

The road ahead 

Still, the broader—and most important—question remains: why do some people respond to immunotherapy, and others don’t? 

Fewer than half of the patients currently selected for treatment respond to therapy, and if they do, it can be short-lived.

A recent study from the University of Michigan Comprehensive Cancer Center revealed it may be molecular changes within a tumor that prevent immunotherapy drugs from killing off cancer. According to the paper, clinical trials with PD-L1 and PD-1 blockade suggested tumors with a high number of inflammation-causing T cells were more responsive to the immunotherapy-based PD-L1 and PD-1 inhibitors. Tumors with low inflammation, or low T cells, were less responsive. But, what controls T cells in the tumor microenvironment is poorly understood—as of now. The researchers believe if they can reprogram this epigenetic mechanism, immunotherapy might work for an increased number of patients. 

Additionally, a group of researchers from the University of California Los Angeles are exploring what causes cancers that shrink in response to PD-1 checkpoint inhibitors to eventually start growing again. A pilot study of patients with melanoma suggested that mutations in certain immune-related genes may be responsible for development of resistance to PD-1 blockade.

“There seems to be a degree of exclusivity as to who responses to immunotherapy,” Sholl said. “It is going to be important for us to know the status of biomarkers to know the right patients for the right drugs, and not just throw immunotherapy at everyone. It seems like it works great in a small subset, but that’s the thing, it’s a small subset.”

Rosenberg agrees better patient selectivity is important, and he views one of the keys to accomplishing this as a more rapid timeline. 

“There needs to be a focused effort on understanding mechanisms of immune escape, and ways to detect those mechanisms; either in the blood or in tumor tissues of those patients so we can come up with tests to predict in advance or understand early on in the course of treatment if things are going to work or not,” he explained. “Instead of waiting three to four months to figure out if immunotherapy is working, [we] might be able to tell in weeks.”

Research presented at ASCO 2016 showed just that: evidence of an immune response in patients who do well with immunotherapy at the three-week mark. 

“If we can turn those type of findings into robust clinical tests, we may help our patients a lot by being able to change course quickly,” Rosenberg concluded.