April 1, 2018 (Vol. 38, No. 7)
Chris Palmer Ph.D. Contract Writer National Institute of General Medical Sciences at NIH
Researchers Contextualize Immuno-Oncology Mechanisms to Advance Personalized Therapies
Cancer immunotherapy focuses on harnessing the remarkable power of the immune system to detect and destroy cancer cells. Immunotherapy drugs, such as antibodies, make cancer cells more vulnerable to destruction by T cells. The leading immunotherapy drugs are checkpoint inhibitors, which act on immune checkpoints, molecular pathways that evolved to prevent T cells from attacking healthy tissue. These pathways, however, can also give tumors a way to evade immune system regulation.
A typical immunotherapy drug is nivolumab. It targets a checkpoint protein on the surface of T cells called programmed cell death protein 1 (PD-1). When PD-1 binds to its receptor protein PD-L1, which is found on the surface of some cancer cells, the T cell becomes inactivated and the cancer cell avoids assault. By binding to PD-1, nivolumab prevents the protein from binding to PD-L1, thereby exposing the cancer cell to an attack by the immune system. Other approved drugs take the approach of directly targeting PD-L1 on the cancer cell.
Because so many patients do not respond to these therapies, researchers are now testing several drugs in combination. By combining immunotherapies, or pairing them with chemotherapy or radiation, researchers are looking to boost clinical benefit.
Early trials of combination therapies have been fairly straightforward. For example, over the past two years, trials pairing drugs targeting PD-1 or PD-L1 with another drug have more than doubled.
Some researchers, however, are starting to explore approaches to more personalized combination therapies. Such approaches might incorporate assessments of the entire cancer microenvironment, assessments that could help clinicians identify the drug combinations that would work best for individual patients. Clinicians might select compounds that would, in combination, boost the immune system or prepare patients for follow-on therapies such as antitumor drugs.
These possibilities were discussed at the recent Tri-Med Conference in San Francisco, which included a track on cancer immunotherapy. Several of the scientists from this track have since shared their cancer immunotherapy insights with GEN.
“Everything is driven by the success of PD-1 and PD-L1,” said Christina Furebring, Ph.D., senior vice president, R&D, Alligator Bioscience. “You need to find something innovative and new because so many people are working in this space.”
In an effort to carve out its own territory, Alligator Bioscience is looking beyond the PD-1 pathway, which is currently being targeted by more than three-quarters of all combination therapies. Instead, the Lund, Sweden-based biotech has developed a bispecific antibody, ATOR-1015, to go after the checkpoint receptor cytotoxic T-lymphocyte-associated protein 4 (CTLA-4).
The combination of drugs targeting CTLA-4 and PD-1 is the only FDA-approved combination to date. And while it has been quite effective, the combination has shown strong toxicity, with a large portion of patients suffering side effects such as colitis and diarrhea.
To minimize toxicity, ATOR-1015 targets CTLA-4 along with the costimulatory antibody OX40. The mode of action of OX40 includes suppression of regulatory T cells as well as activation of effector T cells. “We’re really trying to localize the bispecific antibody to the tumor environment by using two targets, which are highly expressed in the tumor compared to healthy tissue,” explained Dr. Furebring.
ATOR-1015 is currently in preclinical development for Phase I clinical trials. The trials, targeting metastatic cancer, are set to begin in Sweden and Denmark in the latter half of 2018.
Pushing on the Gas
Looking even further outside the conventional checkpoint therapies is Jounce Therapeutics. “We have used our translational science platform to identify targets on immunosuppressive macrophages that we believe we may be able to target with antibodies,” said Deborah Law, D.Phil., the company’s chief sceince officer. “By generating and deploying the right antibodies, we hope to switch these macrophages from being immunosuppressive to being more immunostimulatory. That’s one of the ways that we’re trying to address some of these tumors that are not benefiting so well from the current checkpoint therapies.”
This approach has lead Jounce to target the inducible T-cell costimulator (ICOS), which has been prioritized as a target based on preclinical and clinical results that suggest it plays an important role in the immune response to cancer. In patients treated with ipilimumab, the anti-CTLA-4, ICOS was upregulated. In addition, mice lacking ICOS did not respond as well to anti-CTLA-4 treatment regimens.
Jounce’s JTX-2011 is an ICOS agonist antibody designed stimulate T effector cells and reduce intratumoral T regulatory cells. “You can think of it in contrast to the PD-1s and CTLA-4s, which are thought to release the brake on the immune system,” Dr. Law suggested. “This is more like pushing on the gas.”
According to Dr. Law, the JTX-2011 antibody has the potential to be a combination partner of choice because other agents, such as anti-PD-1 and anti-CTLA-4 drugs, can induce ICOS activity, and then JTX-2011 can bind and provide additional potential antitumor benefit. She pointed out that Jounce is also working on its own anti-PD-1 drug, JTX-4014, to give the company “optionality.”
Combining Checkpoint Inhibitors and Small Molecules
“Small-molecule modulation of the tumor microenvironment is really important for combinations with checkpoint inhibitors,” noted Jonathan Pachter, Ph.D., chief science officer, translational research, Verastem. At Verastem, scientists are developing two primary small-molecules drugs: defactinib, a focal adhesion kinase (FAK) inhibitor, and duvelisib, a phosphatidylinositol-3-kinase (PI3K)-δ/γ inhibitor.
FAK has many kinase-dependent and kinase-independent functions, including control of cell movement, invasion, survival, and gene expression. This protein is overexpressed in cancers that have high invasive and metastatic capability. Verastem currently has three ongoing clinical trials combining defactinib with anti-PD-1 and anti-PD-L1 drugs for use against solid tumors.
Verastem is also exploring the PI3K signaling pathway, which is a key regulator in cancer proliferation and metastasis. In preclinical models, research has shown that PI3K-δ inhibition confers selective inhibition of regulatory T cells, while PI3K-γ inhibition confers selective inhibition of myeloid-derived suppressor cells.
Verastem’s duvelisib is a potent and selective oral small molecule inhibitor of PI3K-δ and PI3K-γ, asserted Dr. Pachter, who added that the company recently successfully met its endpoint for a Phase III trial evaluating the safety and efficacy of duvelisib versus ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The FDA has since granted fast-track designation to the investigation of duvelisib for certain CLL patients.
“We think the dual inhibition of PI3K-δ and PI3K-γ together is really important in the immuno-oncology space,” declared Dr. Pachter. “The ability to suppress those multiple populations is unique to the drug and is quite exciting.”
Data in Context
Research laboratories looking to jump into the combination immunotherapy space or further augment their knowledge of the field can turn to various kinds of firms, including software information companies. One such company, Clarivate Analytics, surveys the current biomedical research landscape and helps researchers develop strategies for identifying new combinations.
“The big challenge in coming up with effective combination therapies is finding good targets,” said Matthew Wampole, Ph.D., the company’s solution science manager. “Beyond PD-1 and CTLA-4, there are several other targets that could potentially be useful but understanding their impact on the immune system and how it responds to tumors still needs a lot of research. This is where Clarivate is helping different groups get more of the context.”
Dr. Wampole added that while there are groups that are trying the “kitchen sink” method, trying every combination they can think of, many researchers are taking a more data-driven look at what might actually be useful for different cancers. “If you understand the particular disease a little bit better,” he maintained, “you can really get more into the precision medicine approach where people are looking at things like the impact of T cells versus that of B cells, or the impact of different effector T cells versus that of M2 macrophages.”
“In immuno-oncology, the whole problem is really the heterogeneity of the tumor and surrounding tissue,” said Alessandra Cesano, M.D., Ph.D., chief medical officer, NanoString Technologies. “The environment—including analytes such as DNA, RNA, and protein—essentially shapes the dynamics and depth of the immune response.”
To provide researchers with the information they need regarding the complex interplay of the tumor, microenvironment, and immune system, NanoString offers the PanCancer IO 360 Gene Expression Panel. The 770-gene expression panel identifies what is driving tumor growth and how the immune system is responding. It includes the 18-gene tumor inflammation signature that NanoString identified in collaboration with Merck & Co. In addition to helping characterize disease biology, the panel allows for possible identification of responder and nonresponder populations for immunotherapy research.
“Another primary challenge in cancer immunotherapy is data integration,” Dr. Cesano commented. “For example, relevant knowledge from the translational field may need to be transformed, essentially, into one single piece of information that can be actionable at the end.”
To facilitate data integration, Nanostring has also developed a Digital Spatial Profiling platform that can enable immuno-oncology applications that characterize highly multiplexed RNA and protein targets in tumor tissue. The platform uses oligonucleotide barcodes with photocleavable antibodies to tag proteins and genes. The technology will enable spatial quantification of protein and gene expression.
Over the past 30 years, cancer immunotherapy has shown great promise, but few cancer immunotherapy drug candidates have passed muster with the FDA. The approved molecules induce nonspecific immune stimulation by preventing T-cell inactivation.
Vaccines have also been used extensively in clinical trials but have faced several challenges, including the choice of antigens and the lack of a potent adjuvant. Sipuleucel-T (Provenge®) has been authorized to treat prostate cancer patients with bone metastasis. MaxiVAX uses a unique approach to treat cancer that relies on a patient-specific cell therapy coupled with the sustained activation of the immune system, says Dimitrios Goundis, Ph.D., the company’s CEO.
A patient’s own tumor cells are used to ensure the most specific and widest antigenic repertoire. Lethally irradiated autologous cancer cells are then injected subcutaneously. This strategy circumvents some of the weaknesses observed with selected peptide vaccines, and all patients and tumor types are potential candidates, asserts Dr. Goundis. Co-administration of a very immune-stimulatory signal is critical.
“Using cell-encapsulation technology, MaxiVAX manufactures biocompatible capsules containing genetically modified cells that can release stable and sustained amounts of immune-stimulatory molecules at the site of immunization,” explains Dr. Goundis. “This approach could not have been realized by previous strategies. Encapsulation prevents the rejection of MVX-1, an allogeneic cell line that produces and releases the potent adjuvant GM-CSF at the site of immunization, for several days.”
Rapid Cell Expansion for Immunotherapy
With today’s exciting advances in immunotherapy come some serious challenges. The realities of low starting volumes and variable samples, for example, can limit the patient population that might participate in promising cell immunotherapies. To overcome these challenges, it is necessary to achieve the rapid expansion of therapeutic cells such as T cells and natural killer cells while maintaining high viability and avoiding the use of exogenous activating compounds. In addition, check point receptor expression is changed in a tumor micro environment. Understanding these changes can help provide a deeper understanding of the checkpoint inhibitor response.
These challenges may be met if culture conditions are properly controlled. Traditional incubators control oxygen, but that is only half of the equation.
“The ability to control pressure as well as oxygen better mimics the human cell environment,” says Rebecca Rutherford, Ph.D., director of operations at Xcell Biosciences. “Tuning both variables has achieved consistent growth regardless of patient variability, cell expansion at high densities, and the ability to selectively enrich for the naive and memory cell populations, among others. Controlling both oxygen and pressure better regulates cell state by tailoring gene, protein, and metabolic profiles of the cells.“
These advances can result in an increase in the patient pool for better phenotyping and profiling, continues Dr. Rutherford, who adds that recreating native microenvironments can greatly enhance immune cell expansion. “In addition, this rapid expansion significantly shortens vein-to-vein time, improving the patient experience,” she points out.
Chris Palmer holds a Ph.D. specializing in neuroscience. In addition to being a freelance writer he is also a contract writer for the National Institute of General Medical Sciences at NIH.