NEW CANCER PIONEERS

More than 50 years ago, the introduction of chemotherapy heralded a new age in the treatment of cancer. Since then and in the past 20 years specifically, cancer researchers have made additional leaps forward in the development of novel therapeutics. Many notable newer treatments focus on commandeering the immune system to combat cancer. Immunotherapies such as anti-CTLA-4 and anti-PD1 antibodies, as well as bispecific T-cell engagers (BiTEs) and chimeric antigen receptor (CAR) T-cell therapies, have made waves in oncology and are moving the field closer to a cure.

"I think we are in a new era with immune therapies," said Sir David Lane, PhD, chief scientist at the Agency for Science, Technology and Research in Singapore. "In some cases, they really do seem to 'cure' cancer, and everyone in the community is galvanized by this."

Other promising areas involve engineering viruses and bacteria to selectively target tumor cells and boost the immune system, or developing novel delivery systems that can transport existing drugs to tumor sites more efficiently and safely. Projects also focus on expanding the druggable genome by creating innovative small-molecule inhibitors.

Such work may be closer to the bench than the bedside, but if successful in the future, it could help transform cancer therapy.

"There are so many interesting and worthwhile efforts in cancer research," said Martin Drysdale, PhD, head of the Drug Discovery Program at the Cancer Research UK Beatson Institute in Glasgow.

Here, Medscape profiles the work of a handful of contemporary investigators who are pursuing promising treatment approaches that stand to have an outsize impact on the future of cancer treatment. One approach has already revolutionized treatment—immune checkpoint blockade—but a number of other, more far-reaching and experimental treatments, such as oncolytic viruses and nanomedicine, are also highlighted

Immune Checkpoint Blockade

In the late 1980s and early 1990s, therapeutic anticancer vaccines had largely failed to mobilize the immune system to attack cancer cells.

James Allison, PhD, then at the University of California, Berkeley, believed that there was a missing link in our understanding of the immune system. Anticancer vaccines had focused on stimulating an immune response by signaling an antigen on T cells called CD28. But what people hadn't realized yet and what Dr Allison had begun to suspect was that negative signals, which help keep the immune response in check, also existed. Dr Allison thought that such brakes to the immune system could explain why vaccines against cancer hadn't been successful.

Soon Dr Allison verified his suspicion. Researchers in France had recently identified an antigen called CTLA-4 on the surface of T cells, which turned on only after T cells became active. "The timing of CTLA-4 activity was a big clue," Dr Allison said.

Indeed, Dr Allison found that CTLA-4 inhibited the immune response and that this "off" signal could be exploited to treat cancer.^[1]

"It makes sense that our bodies have a mechanism to stop an immune response," Dr Allison said. "I realized that CLTA-4 might shut down T cells before they could completely eliminate a large tumor mass, and blocking this negative signal from CTLA-4 could disable the brakes to the immune system and allow T cells to keep working."

To test the idea, Dr Allison, along with postdoctoral fellow Dana Leach, PhD, and graduate student Max Krummel, PhD, conducted experiments in which they injected mice with tumor lines and then treated them with antibodies to CTLA-4. "We saw the tumors just melt away," Dr Allison recalled.

Notably, the CTLA-4 antibodies worked on many different kinds of tumors and even promoted tumor memory—and thus immunity—when mice were re-exposed to tumor cells. These compelling results in mice were first published in Science in 1996.^[2]

"We were not treating the tumor cell, we were treating the immune system," said Dr Allison, now chairman of the Department of Immunology at the University of Texas MD Anderson Cancer Center in Houston. "This marked a radical departure from the current thoughts about cancer therapy. And it was a radical departure from traditional immunotherapy because we weren't trying to mobilize the immune system by vaccination with specific tumor antigens, but instead were unleashing T cells to attack whatever the endogenous response was directed to."

The idea of targeting T-cell inhibitory pathways, known as immune checkpoint blockade, eventually led to the development of ipilimumab (Yervoy®), a monoclonal antibody that targets CTLA-4. After a phase 3 trial,^[3] led by Stephen Hodi, MD, from the Dana-Farber Cancer Institute in Boston, showed that ipilimumab prolonged overall survival in patients with metastatic melanoma by an average of 4 months compared with the vaccine alone, the US Food and Drug Administration (FDA) approved ipilimumab to treat metastatic melanoma in 2011.

Ipilimumab was the first drug to show a survival advantage in metastatic melanoma, but perhaps most compelling are Dr Allison's recollections of how ipilimumab saved patients' lives. He described a woman in her 40s who had developed metastatic melanoma and failed to respond to every previous therapy she had tried. When she was given a single dose of ipilimumab in a phase 1 clinical trial in 2001, Dr Allison recalled that her tumor disappeared. Ten years later, in 2011, when Dr Allison visited the woman, she was still cancer free with no sign of disease. In fact, Dr Allison noted that about 22% of patients who had survived up to 2 years on ipilimumab were still alive 10 years later.

"After 2 to 3 years, the survival curve just flattened out," Dr Allison said. "This was a real first in cancer. At about 2 years, patients weren't dying anymore." Because the immune system doesn't distinguish the type of cancer, Dr Allison saw greater potential for immunotherapy as a universal cancer therapy. Indeed, studies have shown that the CTLA-4 antibody can combat a range of cancers, including prostate, ovarian, and renal cancer, and when used in combination with other drugs, appears to improve survival further.

Combination therapies may be the key to broader success. In 1992, researchers in Japan^[4] identified another receptor on T cells, PD-1, and a series of studies revealed that like CTLA-4, PD-1 also inhibited an immune response but did so through a completely different pathway from CTLA-4. In a 2013 phase 1 study published in the New England Journal of Medicine,^[5] when ipilimumab was combined with an investigational PD-1 antibody, nivolumab (Opdivo®), the drugs had an additive effect. Jedd Wolchok, MD, PhD, from Memorial Sloan Kettering Cancer Center in New York, who led these efforts, found that more than half of patients who received both ipilimumab and nivolumab had their tumor shrink by 80% or more. Follow-up data presented at ASCO revealed that 2-year survival was 79% in this group of patients and had reached 88% in a new cohort of 41 patients receiving both drugs.^[6]

In 2014, two antibodies to PD-1, pembrolizumab (Keytruda®) from Merck and nivolumab from Bristol-Myers Squibb, were FDA approved for the treatment of melanoma. And just a couple of weeks ago, on March 4, nivolumab was approved for the treatment of lung cancer.

Given the success of PD-1 and CTLA-4 antibodies, researchers have identified several other inhibitory molecules, such as LAG-3, Tem3, and TIGIT, all of which work in different ways and may enhance existing treatments.

"It's really an exciting time," Dr Allison said. "The advances in basic science have fueled our understanding of cancer biology and the immune system and have allowed us to treat the majority of people with melanoma, which 5 years ago would have been uniformly lethal. The goal now is to raise survival response to as high as we can get it in as many cancer types as we can get it."

CAR T Cells

Along with immune checkpoint inhibitors, another emerging cancer immunotherapy has been making big waves in oncology.

The therapy, known as CAR-modified T cells, takes T cells from a patient, genetically reprograms them with CAR proteins designed to target a tumor antigen, and infuses them back into the patient. Once inserted into the patient, the CAR T cells can detect and kill leukemic cells.

Carl June, MD, and colleagues from the University of Pennsylvania in Philadelphia are one of the groups pioneering this therapeutic effort. The team engineered an HIV-derived lentiviral vector with a CAR that targets the CD19 antigen found on B-cell leukemias, making the T cells leukemia-specific as well as lethal to these tumor cells. The CAR T cells were also modified so that they could replicate and thus hunt for more leukemia cells.

In December 2013, the group at the University of Pennsylvania presented promising results from their clinical trial. In adults with advanced relapsed or treatment-refractory chronic lymphocytic leukemia (CLL) treated with a novel CAR therapy, CTL019, that targets CD19, 15 of 32 had an ongoing partial response and 7 had a complete response. Additionally, in participants with treatment-refractory acute lymphocytic leukemia (ALL), 19 of 22 pediatric patients had a complete response, which continued in 14 patients, and all 5 adults had a complete response, which persisted in 4 patients.^[7]

With more extensive study, encouraging results in patients continued to emerge.

A study published this past October in the New England Journal of Medicine reported that 90% of patients (27 of 30) with relapsed/refractory ALL experienced complete remissions after receiving CTL019, developed in collaboration with Novartis.^[8]

Stephan Grupp, MD, PhD, from the Children's Hospital of Philadelphia (CHOP) and the University of Pennsylvania, presented follow-up data at the 2014 American Society of Hematology (ASH) meeting in December, revealing that 36 of 39 patients (92%) had an initial complete response after treatment with CTL019, and that 6 months later, 70% of children in the study were still cancer free.

On the basis of this promising data, the FDA awarded CTL019 breakthrough status. CAR T-cell therapy represents a "true paradigm shift" in the treatment of blood cancers, Dr June told Medscape Medical News. Two other groups at the leading edge of CAR T cell research—one at the National Cancer Institute working with Kite Pharmaceuticals and another at Memorial Sloan Kettering Cancer Center in New York City in collaboration with Juno Therapeutics—have also revealed compelling results with the CAR T-cell approach.

"This whole field has just exploded," Daniel DeAngelo, MD, PhD, assistant professor at Harvard Medical School and the Dana-Farber Cancer Institute, told Medscape Medical News in October. "It probably represents one of the most exciting therapeutic strategies to be tried in any form of leukemia, let alone ALL, in the last decade or so."

Activating T Cells: Bispecific T-Cell Engagers (BiTEs)

As early as the 1980s, researchers showed that antibodies could provoke the immune system to attack tumors.^[9]Compared with monoclonal antibodies, bispecific monoclonal antibodies can bind to two antigens on different cells and link them together.^[10] But clinical trials in these first-generation bispecific monoclonal antibodies were disappointing, showing limited efficacy and severe side effects.

In the mid-1990s, Patrick Baeuerle, PhD, honorary professor of immunology at the University of Munich, now at Amgen Research (Munich) GmbH, along with Peter Kufer, MD, a cancer immunologist based in Munich, and colleagues developed a class of novel bispecific monoclonal antibodies called bispecific T-cell engagers (BiTEs) that could potentially overcome these issues. BiTEs are fusion proteins composed of two single-chain antibodies joined by a linker. One antibody targets CD3, an antigen on T cells, and the other targets an antigen on tumor cells.

What's innovative about this design, explained Partow Kebriaei, MD, associate professor in the Department of Stem Cell Transplant and Cellular Therapy at the University of Texas MD Anderson Cancer Center, is that "BiTEs cleverly recruit the tumor to the T cell and then activate the T cell to cause tumor cell lysis. Of note, the tumor cell can be brought to the CD3-positive T cells without regard for T-cell receptor specificity or the need for major histocompatibility complex (MHC) class I molecules for activation."

Blinatumomab (Blincyto™), manufactured by Amgen, is the first BiTE to receive FDA approval. Late last year, the FDA granted blinatumomab breakthrough therapy and orphan product designation for the treatment of non-Hodgkin lymphoma and ALL. The drug targets two antigens—CD3 on T cells and CD19, which is expressed on the surface of B cell-derived ALLs and non-Hodgkin lymphomas—and tethers them together, bringing the T cell directly to the cancer cell. The approval is based on the promising results of a phase 2 open-label trial of blinatumomab in 189 patients with ALL.^[11] After two cycles on the drug, about 43% of patients had achieved complete remission or complete remission with partial hematologic recovery.

Currently there are several BiTEs in clinical trials or being constructed, including MT110, which recently completed a phase 1 trial in patients with lung and gastrointestinal cancers.^[

Oncolytic Viruses

With the emergence of modern genetic engineering in the 1990s, researchers began to see new potential in using viruses to combat cancer. Since then, investigators have made great strides in developing oncolytic viruses that not only selectively target, replicate within, and kill tumor cells, but also initiate a robust immune response against the tumor.

John Bell, PhD, a senior scientist at Ottawa Hospital Research Institute, is leading one such effort. Dr Bell and his colleagues at Jennerex Biotherapeutics have developed a poxvirus that replicates specifically within cancer cells.^[13] This oncolytic virus, known as JX-594, has shown promise in phase 1 and 2 trials in patients with hepatocellular carcinoma (HCC), solid tumors, and colorectal cancer. In a 2013 randomized phase 2 trial^[14]published in Nature Medicine, Dr Bell and colleagues found that JX-594 specifically targeted and killed HCC cells and initiated an immune response at both the higher and lower dose. Notably, the virus also prolonged survival: Patients receiving the higher dose lived more than 7 months longer than those on the lower dose. JX-594 probably will be entering phase 3 trials this fall.

"Oncolytic viruses infect and destroy cancer cells, but a huge component of their activity is encouraging antitumor immunity within patients," Dr Bell said. "Although as an oncolytic this virus wasn't specifically designed to stimulate a patient's immune system, we found this attribute was really important to its success."

With this in mind, Dr Bell along with colleagues David Stojdl, Caroline Breitbach, and Brian Lichty have been developing new platforms aimed at igniting a patient's immune system to attack cancer.

"The real excitement may come with some of the next-generation oncolytic viruses we're working on that are designed specifically to stimulate the immune system as well as target the cancer," Dr Dr Bell and his colleagues have engineered a strain of the Maraba virus, called MG1, to selectively kill tumor cells and to prime the immune system to attack them. In a recent study,^[15]the MG1 vaccine displayed oncolytic activity and an ability to boost antitumor immunity in mice with melanoma.

"This is the strongest immune response that we have ever seen for an oncolytic virus vaccine," Dr Bell said. "We're very excited about this virus."

Another advantage to oncolytic viruses is their minimal toxicity. The primary side effects appear to be fever and flu-like symptoms that resolve quickly, an incredible advantage over the often dramatic side effects associated with chemotherapy agents.

More than a dozen other oncolytic viruses have reached the early clinical trial phase, either as a single agent or in combination with chemotherapy, and many others are being developed and tested in preclinical models. Oncolytic viruses already in clinical trials include Reolysin®, developed by Oncolytics Biotech to treat a range of cancers such as melanoma and pancreatic cancer; GL-ONC1, made by Genelux to combat peritoneal carcinomatosis and solid tumors among others; and the Seneca Valley virus (NTX-010) to target lung cancer and neuroendocrine tumors.

Dr Bell noted that combining different therapies will be where the biggest breakthrough emerges. "A combination of viral therapeutics and checkpoint antibody inhibitors will likely provide the greatest benefit to patients in terms of initiating a strong immune response and killing tumor cells," Dr Bell said. "We're in a good position to provide these combinations because many important therapies are maturing at the same time."

Nanoparticle Delivery System

For years, researchers have been looking for ways to overcome the major issues associated with existing cancer treatments, namely specificity, efficacy, and toxicity. Nanoparticle technology holds great promise for surmounting these challenges and potentially elevating the effectiveness of chemotherapy drugs.

In the past few years, efforts in nanotechnology-based therapeutics have accelerated with a range of new agents showing efficacy in clinical trials and several on the cusp of FDA approval.

"The initial goal of our work was to create a delivery system that could chaperone a drug directly to the sites of tumors and protect it along the way," said John W. Park, MD, professor of medicine at the University of California, San Francisco (UCSF), who has pioneered a number of these anticancer nanoparticles.

Several innovative approaches to nanomedicine exist, some of which use gold, silica, or quantum dot nanoparticles, but Dr Park's strategy is to use a durable, well-understood liposome-based matrix that can securely encapsulate and deliver a drug to the tumor site.

"The robustness of the nanoparticle is key," Dr Park said. "We don't want the drug to be released or to degrade prematurely. We want a stable structure that can effectively and efficiently deliver the payload."

One such nanoparticle delivery system developed by Dr Park and colleagues, MM-398, recently completed a phase 3 trial for patients with metastatic pancreatic cancer. MM-398, manufactured by Merrimack Pharmaceuticals, was engineered to carry the chemotherapeutic agent irinotecan. In the phase 3 NAPOLI-1 (NAnoliPOsomaL Irinotecan) trial, patients with metastatic pancreatic cancer were randomly assigned to receive MM-398, a combination of 5-fluorouracil and leucovorin, or MM-398 plus the combination therapy. The investigators found that the group receiving MM-398 plus the combination had the best response, showing greater overall and progression-free survival compared with the other two arms. On the basis of these promising results, Merrimack is filing a new drug approval (NDA) with the FDA.

The MM-398 platform is also being investigated to target gliomas. Although only just entering clinical trials, the preclinical results are promising. UCSF investigators are employing convection-enhanced delivery, which can overcome issues associated with crossing the blood-brain barrier by infusing the nanoparticle-based drug directly into the tumor or near the tumor through a catheter. This method of delivering nanoparticles to brain tumors can allow the treatment team to monitor whether the agent is targeting the tumor, which preclinical trials show it does.^[16]

Perhaps the most novel of this portfolio of nanoparticle therapeutics, according to Dr Park, is for breast cancer. MM-302 has a liposome structure that contains doxorubicin, a standard chemotherapeutic for breast cancer, but also links to an antibody that targets human epidermal growth factor receptor 2 (HER2). Thus, the immunoliposome MM-302 is designed to zero in on tumor cells that overexpress the HER2 receptor and to penetrate and release doxorubicin within these cells.

As yet, no targeted nanoparticle has achieved the milestone of FDA approval. However, MM-302 is currently being evaluated in a randomized clinical trial to treat advanced metastatic HER2-positive breast cancer in combination with trastuzumab (Herceptin®).

"This technology can be looked at as an especially potent antibody-drug conjugate that can leverage what antibodies do and combine them with nanoparticle drug delivery," Dr Park said.

Commenting on the future of nanotechnology for cancer, Dr Park hopes that current efforts in nanoparticle-based cancer therapies from his team and from other groups will bring about a new class of agents that can join existing and emerging treatments.

"The nanotechnology vision for cancer treatment is to use new macromolecular structures to make a real difference in cancer treatment," he said. "We are now moving beyond the initial technology and discovery phase, and are seeing clinical proof that these nanotherapeutics can extend survival for pancreatic cancer and have potential to treat many other types of cancers."

Targeting the Elusive: Drugging RAS 

Some of the most common genetic aberrations in cancer remain elusive targets of drug therapy. One such target is the RASgene. Mutations in RAS occur in up to 90% of pancreatic cancers and in about 30% of human cancers overall.

Since late 2010, Martin Drysdale, PhD, of the Cancer Research UK Beatson Institute in Glasgow, has been screening libraries of molecular fragments in the hopes of identifying ones that can bind to the RAS oncoprotein and inhibit its function.

"As the last few years have shown us, these are not targets that will yield particularly quickly," Dr Drysdale said. "We're making evolutionary progress as opposed to revolutionary progress. But we are still in the game."

Dr Drysdale is ultimately hoping to find compounds that inhibit activated RAS by disrupting effector binding, the process by which mutant RAS amplifies its cancer-promoting signals. What's tricky, Dr Drysdale explained, is the structure of RASproteins. The pockets on RAS are shallow, which provides limited opportunity to construct molecules that can directly bind to it. Another difficulty has been building reliable assay systems that can easily screen large numbers of relevant molecules.

An initial breakthrough in directly targeting RAS came when two teams independently reported that it was possible to bind to the oncoprotein KRAS. A group at Genentech screened thousands of small molecules and found 25 compounds that could bind to a pocket on KRAS and block activity of an enzyme, called Son of Sevenless, required to activate the oncoprotein.^[17] After screening a library of 11,000 molecular fragments, a team led by Stephen Fesik, PhD, at Vanderbilt University in Nashville, discovered several fragments that could bind weakly to a small pocket present in the mutated KRAS protein and inhibited its activity.^[18] Still, in both cases, these molecules bound only weakly to KRAS. To become effective drugs, such compounds would need to be engineered to have greater binding affinity and anticancer potency.

"The main problem is being able to build sufficient potency and selectivity for these molecules," said Dr Drysdale. "But work from Genentech and Vanderbilt grabbed people's imagination and went a long way in reinvigorating the challenge of targeting RAS."

To this end, in 2013, the National Cancer Institute launched the RAS Initiative, a collaborative effort that brings together a diverse collection of research groups all working on targeting RAS. Other potentially promising efforts to inhibit RAS directly include targeting a particular mutant of KRAS known as G12C.

"This approach created quite a stir in the field," said Dr Drysdale, pointing in particular to work from Kevan Shokat's lab at UCSF.^[19]

For Dr Drysdale, the most critical factor pushing him and his team forward has been the availability of crystal structures of their compounds bound to RAS.

"Our ability to obtain reliable crystal structures has been transformational in terms of what we can attempt and achieve," Dr Drysdale said. "We have identified two series of compounds for which we have high-resolution crystal structures and are using this information to guide optimization."

But Dr Drysdale cautioned that despite the hype, we're still at the early stages of this work. "None of these things happen overnight," Dr Drysdale said. "But we have a huge opportunity here to discover and build inhibitors of one of the top-level drivers of tumors."