The Promises and failures of cancer immunotherapy

Few ideas in oncology have raised hope of a potential cure for cancer as much as immunotherapy. The treatment is now commonly used in clinics and hospitals, which in itself is a major medical breakthrough, but it’s still a far cry from the magic bullet many expected it would be in the fight against cancer.   

Involving the stimulation of the immune system to fight tumours, the approach has received a heap of praise and media coverage, most of which touted it as a game changer in cancer treatment.

In 2018, Drs James P. Allison and Tasuku Honjo, two of immunotherapy’s pioneers, were awarded the Nobel Prize in Physiology or Medicine for discovering a key way to harness the immune system against cancer.

“For more than 100 years, scientists attempted to engage the immune system in the fight against cancer. Until the seminal discoveries by the two laureates, progress into clinical development was modest. Checkpoint therapy has now revolutionised cancer treatment and has fundamentally changed the way we view how cancer can be managed,” argued the Nobel Assembly at Karolinska Institutet in Sweden in a press release.

With the ability to distinguish the body’s own tissue from foreign substances, the immune system can neutralise invaders, like viruses and bacteria, while sparing the body’s own organs. Integral to this discriminating process are immune checkpoints. These are proteins present on the surface of T cells — the so-called soldiers of the immune system — and can put the brakes on immune cells, thereby preventing them from attacking healthy cells. While some cancers can hijack checkpoint proteins to disguise themselves from the immune system, the Nobel laureates figured out that inhibiting immune checkpoint proteins like CTLA-4 and PD-1 would unleash T cells against tumours.

This led to the development of checkpoint therapy for cancer, which releases T-cell brakes through medications known as checkpoint inhibitors and is currently one of the most effective and widely used immunotherapeutic approaches.

Between 2011 and 2014, the US Food and Drug Administration (FDA) gave the green light to the two first checkpoint inhibitors, ipilimumab and pembrolizumab, after they achieved significant survival improvement or tumour shrinkage in patients with late-stage or metastatic melanoma. Since then, an array of inhibitors has been approved to treat at least 15 malignancies, including lung, head, neck, and colorectal cancers.

“How long patients survive after treatment with checkpoint inhibitors differs from patient to patient and from tumour type to tumour type,” explained Dr Siwen Hu-Lieskovan, Director of Solid Tumor Immunotherapy at the Huntsman Cancer Institute at the University of Utah, to Global Health Asia-Pacific. “For instance, patients with melanoma who respond to [treatment to inhibit the checkpoint protein] PD-L1 see a response lasting for one to two years on average or even longer, and some patients can even be considered cured.”

This is a remarkable feat considering that chemotherapy is not that effective against melanoma while the other main treatment for the disease, targeted therapy, usually gives patients just one year in remission before relapse.

Similarly, recent data show that pembrolizumab increased almost fivefold the percentage of patients with non-small cell lung cancer (NSCLC) who survive five years or more after diagnosis, according to the Cancer Progress Report 2019 by the American Association for Cancer Research.

“Immune checkpoint proteins seem to be part of an important immune escape mechanism for a lot of cancers and that’s why the development of checkpoint inhibitors is a major breakthrough,” said Dr Hu-Lieskovan.

Another immunotherapy that is often hailed as a revolutionary cancer treatment leading to miraculous cures is chimeric antigen receptor (CAR) T cell therapy, “one of the most remarkable advances in cancer therapy in the last several decades,” as doctors from Johns Hopkins University School of Medicine recently wrote in The Lancet.

The approach is a powerful example of living drugs as it’s based on human T cells equipped with a new gene producing the chimeric antigen receptors to give immune cells the ability to attach to an antigen, or protein, present on tumour cells, thereby singling cancerous tissue out for destruction.

Mostly used against some types of blood cancers, including B-cell acute lymphoblastic leukaemia (ALL), the “overall response to CAR T cell treatment is impressive,” Dr Lee Yuh Shan, senior consultant haematologist at Parkway Cancer Centre in Singapore, told Global Health Asia-Pacific.

About 80 percent of children with B-cell ALL, for instance, were cured by chemotherapy or a stem cell transplant, but for the rest there were no effective treatment options available until the advent of CAR T cells. In this segment of patients, the novel therapy achieves an 80 percent remission rate, giving children like Emily Whitehead a glimmer of hope.

While on the verge of death in 2012, Emily was one of the first children with B-cell ALL to be treated with CAR T cells in a clinical trial at the Children’s Hospital of Philadelphia. “I have never seen a patient that sick get better so quickly,” Dr Stephan Grupp, the paediatric oncologist who treated her, told The New Yorker contributor Siddhartha Mukherjee.

With CAR T cells literally pulverising her tumour, she’s already been in remission with no trace of cancer in her blood for at least seven years, according to Mukherjee.

Stories like Emily’s have contributed to an aura of magic surrounding immunotherapy. As is often the case in health journalism, however, the curative power of new treatments is sometimes exaggerated.

In December 2018, the prestigious medical journal The Lancet run an editorial titled Immunotherapy: hype and hope to warn against sensationalism in media reports, highlighting that “results from studies of specifically selected patients, or even just one individual,” are sometimes hyped and “taken as firm evidence of efficacy.”

Such hype can mislead the public into thinking that immunotherapy is effective for every patient to the same, or similar, extent. “Individual patient immunity undoubtedly leads to variation,” the editorial continued, “but outcomes from a proportion of responders and superresponders can dominate top-line data, potentially masking many other patients with less striking results.”

It’s also crucial to remember immunotherapies are not entirely safe and can lead to unwanted side effects that could be serious, such as infection, pulmonary toxicity and diabetes.

“Although there is great promise in immunotherapies, we must not let the excitement of such treatments overshadow their potential for harm. Clinicians, researchers, and patients must be wary of the hyperbole associated with certain professionally marketed studies, and the limitations of off-label use of new drugs. When the associated media coverage of therapies gives patients unrealistic expectations of outcomes, it is increasingly difficult for clinicians to deny immunotherapy, particularly as a last hope for those patients for whom other treatments have failed; however, caution must be exercised, with ‘first do no harm’ being central in decision-making,” the editorial advised.

A reality check

And for all the spectacular improvements cancer immunotherapy has brought about, it’s still a treatment that can benefit only a limited number of patients.

“The response rate to checkpoint therapy is not very high,” said Dr Hu-Lieskovan. “For most indications, we’re talking about a 10 to 20 percent response rate.”

Complex and still unclear mechanisms of resistance allow most cancers to escape the immune reaction ignited by checkpoint inhibitors. The substantial presence of antigens, or substances the immune system recognises as foreign, on tumour cells is an important indicator of checkpoint therapy efficacy as they’re believed to provide immune cells with targets to pinpoint for their anti-cancer activity.

“This is a profoundly game-changing therapy for a minority of patients, not a majority, because it changed the way we treat many types of cancer, though not all of them,” Dr Joshua Brody, assistant professor in medicine, haematology and medical oncology at the Mount Sinai School of Medicine, told Global Health Asia-Pacific.

But even if immunotherapy can help only about a fifth of patients with specific types of cancer, this translates into hundreds of thousands of lives saved or at least meaningfully prolonged, he added.

In the case of some lung cancers, patients treated with checkpoint inhibitors can survive for several more months than those on standard therapies. The study Keynote 024, for instance, showed the drug pembrolizumab gave patients with non-small-cell lung cancer expressing the protein PD-L1 an average of 10.3 months of progression-free survival, significantly improving chemotherapy’s mean of just six months. Not only is checkpoint therapy survival much longer than that seen with chemotherapy, but some patients continue responding to the therapy even after its discontinuation, explained Dr Nagashree Seetharamu, assistant professor in medical oncology at Zucker School of Medicine, in an interview with Global Health Asia-Pacific.

Despite its advantages, however, the efficacy of checkpoint inhibitors can fade away, and many researchers are trying to figure it out why this happens, she added. One hypothesis is that the immune checkpoint molecules currently targeted by drugs on the market are only a limited set, given that over time cancer cells are able to switch to another unknown checkpoint pathway to re-disguise themselves from the immune system.

Cancers that cannot be treated with immunotherapy or whose treatment has not been upended by it include prostate and breast malignancies, some of the most common forms of the disease, as well as rarer cancers like brain tumours.

“Breast cancer is not very responsive to immunotherapy,” said Dr Hu-Lieskovan.  “There’s a combination of an anti-PD-L1 checkpoint inhibitor with chemotherapy that’s approved for some breast cancers, but the response is still pretty low.” Greenlighted by the US Food and Drug Administration in March 2019, atezolizumab plus chemotherapy achieved a median progression-free survival of 7.4 months in patients with triple negative breast cancer expressing PD-L1, while a placebo, or dummy pill, reached 4.8 months. 

Another example of immunotherapy’s limitations is found in brain cancers. These don’t have many antigens and are poorly infiltrated by T cells, making checkpoint therapy ineffective because the immune system lacks enough soldiers to attack tumour cells, said Dr Marta Alonso, brain cancer researcher at the Clínica Universidad de Navarra in Spain, to Global Health Asia-Pacific.

Unlike checkpoint inhibitors, CAR T cell therapy achieves high response rates in some subtypes of blood cancer, but its long-term efficacy is still an open question while its manufacturing process throws up a number of practical barriers for patients.

“CAR T cell therapy is the most important development in immunotherapy for blood cancer and is effective against B-cell ALL, with complete remission in around 80 percent of cases, and large B-cell lymphoma (LBCL), where it elicits a positive response in 50 to 80 percent of cases,” said Dr Lee. However, some patients might not have a durable response, he added.

Assessing several studies, the report Clinical lessons learned from the first leg of the CAR T cell journey found CAR T cell therapy led to “high rates of relapse that limit overall success” in B-cell ALL, according to Medical Express. By contrast, patients with LBCL experienced lower complete response rates than those with B-cell ALL, but they also relapsed more rarely after treatment.

Factors believed to make the therapy ineffective or hinder its curative power include rejection of the infused T cells by the organism, antigen loss in cancer cells, and T cell exhaustion or depletion.    

Producing CAR T-cells takes at least one week and involves the harvesting of patient T cells to be genetically engineered and expanded in the laboratory and subsequently injected back. And since a new customised batch is needed for each patient, they come with a hefty cost, ranging from US$370,000 to 475,000.

Dr Lee believes CAR T cell manufacturing and cost are significant challenges that limit its availability. The complexity in the expansion technique and the shortage of the virus needed to genetically engineer CAR T cells, for example, mean that only a few centres across the world are currently equipped to produce the living drugs.

“Unless we find a better way of managing the production and cost of CAR T cells, it’ll be hard to make the therapy available for most of the public,” he said.

Dr Nabil Ahmed agrees that these are real challenges, but he’s confident a new generation of CAR T cells will solve them.

The key problem with CAR T cells is the need for an individualised product made of the patient’s own immune cells to avoid their rejection by the organism once they’re infused back into the body, he explained. One solution currently being tried is to churn out universal CAR T cells from donor tissue that can be used for treating any patient without the risk of rejection.

“Using allogenic CAR T cells will streamline the manufacturing process and bring down costs,” he said.

An immunotherapy researcher at the Baylor College of Medicine, Dr Ahmed is currently testing the use of CAR T cells in solid tumours like brain cancer and sarcoma, a malignancy that can grow in several types of tissue, such as bones, muscles, and fat. If successful, this will open up CAR T cell therapy for a much greater number of patients.

In a series of clinical trials, Dr Ahmed’s team established the safety of high doses of CAR T cells in patients with glioblastoma, one of the most common types of brain cancer and a hard-to-treat malignancy, and observed tumour stabilisation in both glioblastoma and sarcoma. In one study, two out of 10 patients with sarcoma managed to stay in remission for about three years — a significant improvement considering they were deemed incurable with no treatment options available.

Further investigations are needed to prove the therapy is an effective option to kill those cancers, but establishing safety is an important first step because CAR T cell infusion can lead to potentially serious side effects, like cytokine release syndrome (CRS) and neurotoxicity.

CRS is caused by the excessive production of cytokines, chemicals released by T cells to direct the immune response against cancer, and produces dangerously high fevers and a drop in blood pressure. Serious CRS affects about 46 percent of patients with relapsed B-cell ALL, while the rate drops to 13 to 18 percent in patients with relapsed LBCL, said Dr Lee.

“Patients who develop CRS require close monitoring, but there are established guidelines to manage the condition effectively,” he added.

The other side effect, neurotoxicity, involves seizures and mental confusion, but these can be treated with steroids and medications.

Checkpoint inhibitors come with some risks as well.

More than 90 percent of patients on PD-1 checkpoint inhibitors, for instance, will see minor or no toxicity at all, according to Dr Hu-Lieskovan. Common problems include rashes, diarrhoea, and fatigue.

But in rarer instances, patients can develop more serious conditions. “When toxicity happens, it can happen everywhere, and we cannot predict the patients who’ll suffer from it nor which organ T cells will attack. Sometimes it’s a really bad rash, sometimes it’s hepatitis or even more severe conditions like type 1 diabetes or myocarditis, an inflammation of the heart muscle that could even lead to death,” she said.

New frontiers in immunotherapy

While several lines of research in oncology revolve around improving the efficacy and safety of checkpoint inhibitors and CAR T-cell therapy, there are also many other immunotherapeutic approaches currently under development that offer hope for people with cancer.

With some evidence suggesting that gut bacteria play a role in the response to immunotherapy, many researchers are trying to identify what increases the chances of positive treatment outcomes.

In patients with melanoma treated with anti-PD-1 immunotherapy, for instance, better responses to treatment were associated with consumption of a high-fiber diet and gut microbiome diversity, according to a study presented at the American Association for Cancer Research Annual Meeting 2019.

“We found that diet and supplements appear to have an effect on a patient’s ability to respond to cancer immunotherapy, most likely due to changes in their gut microbiome,” said Dr Christine Spencer, research scientist at the Parker Institute for Cancer Immunotherapy, in a press release. “The gut microbiome plays a big role in moderating the immune system, so the idea that we could potentially change the microbiome — whether by diet or other means — to improve response to immunotherapy treatment is really exciting.”

When it comes to other immunotherapeutic treatments, an interesting and potentially fruitful method is in situ vaccination, where a highly specific anti-cancer vaccine is created right inside the patient’s tumour.

Most vaccines are manufactured in the lab by putting together a biomarker of the disease in question that acts as target and an immune stimulant, explained Dr Brody. The final product is then injected into patients to train the immune system to recognise and get rid of the disease.

In situ vaccination, in contrast, involves only the injection of the stimulant coupled with either a virus or radiation to injure the tumour and make it release its antigens. A loaded immune system is then able to identify those antigens, creating a vaccine on site that attacks cancer cells.

Using a similar approach in a clinical trial, Dr Brody’s team treated patients affected by low-grade lymphoma with low-dose radiation, then injected a first immune stimulant called FLT3L, followed by an injection of a second stimulant, the TLR agonist. The use of FLT3L is the distinguishing feature of this in situ vaccine and its role is to bring an increased number of immune cells to the tumour for activation, thereby increasing the potency of the vaccine.

In some patients, the results were astounding. “In persons with tumours all over their body, we saw almost all of them melting away,” said Dr Brody. “Although we don’t call this a cure, those patients certainly went into remission and we are now checking how long this can last.”

Only four out of 12 patients went into significant clinical remission, however, while the rest saw only minor improvements in some of their tumours.   

Chemotherapy, the standard treatment for low-grade lymphoma, can put patients in remission for years, but the downsides include hair loss and increased risk of serious life-threatening infections. Eventually, patients pass away because the disease isn’t curable, and they can’t tolerate increasingly high doses of chemotherapy.

“So far, we can’t say in situ vaccination is as powerful as chemotherapy but is definitely much better tolerated as its common side effects are a one-day flu or fever,” said Dr Brody. “Maybe if we give people the vaccine over and over again once cancer recurs, we could keep patients in remission as long as chemotherapy does, but we haven’t had the chance to test this yet.”

The team’s next goal is to make the vaccine more powerful by combining it with checkpoint therapy.

In another part of the study conducted on mice with lymphoma, the combined administration of the two immunotherapies showed to be a more effective treatment than their separate use. “Checkpoint blockade is not an effective treatment for lymphoma at all, while in situ vaccination cured about 45 percent of animals,” he said. “But the two of them together managed to cure about 85 percent of mice.”

The team has already set up a clinical trial to test the two approaches together in patients with lymphoma, breast, head, and neck cancers, and preliminary data have shown positive results.

“I think it’s a promising time for in situ vaccination because people are realising that, besides putting the brakes off the immune system with checkpoint inhibitors, we also need to tell it what to do through a vaccine, not just cut the brake pedal but steer the steering wheel too,” he quipped.

Combination is now one of the most uttered buzzwords in the research community since there are swathes of data indicating that giving patients multiple immunotherapies tends to increase treatment potency.

This holds true for another form of immunotherapy called oncolytic viruses, the practice of using attenuated viral pathogens to infect and kill tumour cells in a process that also leads to an immune response against cancer.

In a clinical trial conducted by Dr Alonso and other researchers at MD Anderson Cancer Center in the US, a modified version of the Delta-24-RGD adenovirus, which infects humans with the common cold, proved to be a powerful treatment option for some patients with recurred glioma, an umbrella term for several types of brain cancers common among adults. In order to make it more cancer-specific, the virus was tweaked in the lab to give it the ability to only replicate in cancer cells.

While being alive six months after recurrence is usually considered a good survival for patients with glioma, the viral treatment allowed about one fifth of the 32 participants to survive for three to four years with minimal side effects like mild fever or flu. “The good thing about oncolytic viruses is the lack of toxicity, especially compared to other types of immunotherapy like immune checkpoints, which have much more adverse effects,” said Dr Alonso.

Despite their favourable benefit-to-risk ratio, oncolytic viruses require much improvement if we want to increase life expectancy and benefit a larger number of patients in one of the most deadly forms of cancer. And combining them with checkpoint inhibitors is a promising way to buttress their efficacy.

“The results we have observed are very promising, but I think the virus will have to be combined with another immunotherapy like dendritic cell vaccination or checkpoint inhibitors because the virus attracts a lot of lymphocytes to the tumour site,” said Dr Alonso, hinting that those immune cells would have a stronger anti-cancer activity if, for instance, their brakes were cut off by checkpoint therapy. In fact, there’s already at least one clinical trial showing that the combined use of Delta-24-RGD with pembrolizumab outperforms both approaches when they’re used as stand-alone treatments.

“The work ahead for brain cancer involves combinations of immunotherapy,” she stressed. “We have to improve oncolytic viruses to make them more potent because we know they’re safe and so that more patients can benefit from their curative effect.”

In yet another example of the great deal of attention researchers are paying to immunotherapy combinations, Dr Hu-Lieskovan is now supervising a clinical trial testing the oncolytic virus Talimogene laherparepvec (TVEC) in combination with PD-1 inhibitors. TVEC is already being used in the clinic as a stand-alone treatment for melanoma as it can induce local responses even in huge tumours, she explained, but it’s less effective than PD-1 inhibitors. Promising data suggest that its combined use with checkpoint therapy could lead to better outcomes.

“One general consideration is that, no matter how you activate the immune system, when T cells attack tumours they can encounter the PD-1 checkpoint [and use it to put the brakes on the immune system], therefore anti-PD-1 inhibitors are the backbone of combination immunotherapies,” she stressed.

But as the fight against cancer has already taught us, there won’t be a one-size-fits-all solution.

“There are hundreds of immunotherapy combinations, and the reality is that none of them has proved to be super effective,” she said. “The challenge is that different people have different mechanisms of resistance to therapies. For this reason, the hottest area of research is to figure it out how to select the right patients for each combination.”

In the search of the best approach for steering the immune system in a way to best fight cancer, researchers have found that one key positive of in situ vaccination and oncolytic viruses is that they can be easily manufactured and translated into a ready-made treatment, gaining a significant edge over made-to-measure immunotherapies like CAR T cell therapy in terms of production time and cost.

“In situ vaccination is an off-the-shelf therapy that is personalised for each patient because it’s injected directly into tumours, making specific vaccines for their antigens,” said Dr Brody. “But it’s much easier to manufacture than any individualised immunotherapy and therefore it should be much cheaper as well because you don’t need to do a new batch for every patient.”

This is a practical aspect that can’t be ignored, given rising healthcare costs, especially in cancer treatment, and the growing number of patients facing financial ruin as a result.

“The healthcare system in America and around the world has been stressed by some powerful but expensive new cancer therapies, so it’s hugely important to have practical and inexpensive ways to treat cancer,” he said.

This article was originally published in print in January 2020.