Cancer Special Report: Body, heal thyself

To attack cancer, researchers are tapping evolution’s weapon of choice: the immune system

Register for free to listen to this article
Listen with Speechify
0:00
5:00
In the mists of time and mythology, Hercules faced many challenges as he bridged the netherworld between man and gods. One such challenge was the destruction of the hydra, a many headed beast with incredible regenerative capabilities. No sooner would Hercules remove one head and turn to the next set of snapping jaws than the first would heal and form two new menacing heads.
 
In many respects, oncologists face a similar challenge when it comes to the treatment of cancer. No sooner do they treat a patient with one modality or another than the disease regenerates itself, morphing just enough to evade destruction time and again. For this reason, many cancer patients go through round after round after round of treatment.
 
Advances in radiation therapy and chemotherapy, as well as the identification of cancer-specific molecular markers and the advent of biologics, have done much to improve an oncologist's weaponry against many cancers. But in many ways, oncology has reached a stalemate where chronic disease is considered an improvement over fatal disease.
 
Even here, the hydra-like rapidity with which cancer cells reinvent themselves keeps oncologists doing their best to switch tactics just as quickly, but with diminishing returns. If only they had a resource that could match cancer’s quicksilver heterogeneity move for move.
 
Evolution, it seems, has taken care of that. Meet the immune system.
 
Tapping immunity
 
“The immune system is a very elegant system that has evolved over millions of years,” says Cenk Sumen, manager of technology and business development at PCT, a Caladrius company, a contract development and manufacture company focused on cell-based therapies. “T cells are very good at matching up their receptors with the MHCs on the dendritic cells.”
 
PCT and its parent company Caladrius Biosciences, formerly NeoStem, are part of a rapidly growing industry that is looking for ways to tap into the natural function of the immune system and either give a patient’s inherent system a boost or initiate the reaction from the outside. The idea is that the massive molecular changes a cancerous cell or tissue undergoes make it as much a foreign body within a patient as a bacterium or virus.
 
“If one successfully engages and turns the patient’s immune system to attack the cancer cells, and in a way that can overcome the immunosuppressive environment that is built up by cancer cells … there is nothing more powerful as a cancer therapy than this,” offers Christian Rommel, head of drug discovery, oncology discovery at Roche.
 
“So the T cell, when it establishes the immune synapse or engages the target cell—let it be a virus, bacteria, cancer cell—it establishes this lethal interaction, then there is nothing to hold it back from killing everything in front of itself,” he continues, but then adds a factor that is unique to immune-centered therapies or immunotherapies.
 
“Second, there is a lasting response that is amplifiable, which other therapeutics can’t do, and there are opportunities to build in memory control.”
 
The importance of this memory control is highlighted in a widely circulated pair of graphs suggesting patient performance on therapies that target the cancer versus therapies that stimulate the immune system.
 
As Padmanee Sharma and James Allison of the MD Anderson Cancer Center recently explained in a Cell review paper, therapies that target molecular identifiers unique to or prevalent in cancer cells (e.g., HER2) often offer remarkable clinical responses in a broad patient population, but those responses aren’t always long-lasting.
 
“The ability of cancer cells to adapt to these agents by virtue of their genomic instability and other resistance mechanisms eventually leads to disease progression in the majority of patients nonetheless,” the authors suggested.
 
In teaching the body how to defend itself against the malevolent forces within using immunotherapies, however, the belief is that any efficacy will be more sustained and that the body will be ready to ramp up new defenses at the first sign of cancer recurrence.
 
But even with the immune system, cancer is not ready to give up so easily, and there are several mechanisms by which tumors protect themselves from an endogenous immune response, including interstitial gradients that keep antibodies out and the release of immune inhibitory substances (e.g., cytokines, galectins, gangliosides).
 
“In addition to these adaptive inhibitory mechanisms, there are also other cells that are already there in the tumor microenvironment, immunosuppressive cells like suppression-associative macrophages, all types of myeloid-derived suppressor cells, regulatory T cells (Tregs),” Rommel adds. “So removing or interfering with these suppressive mechanisms may turn out to also be very important to combine with the approaches that generate the T cell specificity for the tumor.”
 
“Cancer immunotherapy basically means engaging therapies that are specifically designed to engage the immune system to attack cancer,” reiterates Pablo Umana, head of cancer immunotherapy discovery at Roche. “But in the majority of cases, you would need to generate an immune response to generate new immune effector cells that would recognize the tumor; for example, a cancer vaccine or some other therapy that induces immunogenic cell death.
 
“And in those cases, if you want the body to generate an immune response, most likely with the release or the exogenous presentation of the tumor antigens, you will also have to give some strong stimulation of the antigen-presenting cells (APCs) so that they can prime the T cells to generate an immune response.”
 
And further complicating this already-complicated challenge is that not all tumors are ready for their immunological close-ups. The inflammation state of a tumor can also impact how well the immune system recognizes it as a foreign invader.
 
Thus, interventions with things like checkpoint inhibitors (see more below) may not be enough.
 
“Even in that group of inflamed patients, which represents up to about one-third of cancer patients, there are subgroups of patients where you will need to add something in addition to the checkpoint inhibitors to have even deeper and long-lasting responses,” explains Umana.
 
“And then there is the larger group of patients, the ones that have non-inflamed tumors, where you do not already have those T cells present in the tumor, where immune checkpoints inhibitors don’t work at all,” he continues. “What we need to do there is to get those tumors inflamed so then we can then use an immunotherapy approach to drive an immune reaction against those tumors.”
 
With this daunting task in mind, several immunotherapy approaches have been developed that either alone or in combination may help in the battle against cancer.
 
Going viral
 
One way to target cancer is to use a virus that will selectively infect and destroy the tumor cells, reproducing other viral particles that go on to infect neighboring cancer cells—the oncolytic virus approach. But more than simply attacking the tumor cells, the virus also helps the immune system see the cancer.
 
As the oncolytic virus replicates in the tumor, antigens released from dying cancer cells are exposed to the patient’s immune system, triggering an immunological cascade that infiltrates and further destroys the tumor with the added benefit of immunologic memory.
 
The first generation of oncolytic viruses were not particularly efficacious, however, as the scientific community had concerns about unleashing a pathogenic product into a patient’s body.
 
“In those early days, people were quite concerned about oncolytic viruses, and they tended to make them very attenuated,” explains John Beadle, CEO of PsiOxus Therapeutics. “In fact, what they were trying to do was to make them very selective for cancer and not kill normal tissues. So scientists would modify the genes of these viruses, and in the process, make them very weak.”
 
Seeing the challenges of the early-generation viruses, he continues, the researchers that developed PsiOxus’ leading product used directed evolution to create a much more potent cancer-specific virus.
 
“The idea here was to create a large randomly created chimeric library of viruses … take as many different adenoviruses as you could get hold of, force them to recombine in random ways that would create chimeric viruses consisting of different genetic material and then try to grow all of those resulting daughter viruses on cancer cells,” he relates.
 
Once they identified a set of clones very potent at killing cancer cells, they screened those viruses back against a panel of normal cells, looking for those unable to replicate.
 
The resulting product—enadenotucirev or EnAd—is specific for solid tumors of epithelial origin (e.g., colon, breast, pancreas, prostate, non-small cell lung cancer) and is in early-stage clinical trials against many of these cancers.
 
And PsiOxus is not alone in the pursuit of oncolytic viruses, with companies like Amgen and MedImmune taking active roles in this area.
 
In January, MedImmune announced a licensing agreement with Omnis Pharmaceuticals for access to the latter’s oncolytic virus program centered on a genetically engineered vesicular stomatitis virus. The goal, according to Omnis CEO Stephen Russell, is to find synergies between MedImmune’s immunotherapy program and Omnis’ virus to improve the potency of the combination.
 
“We are taking advantage of the immense ‘intelligence’ of viruses and the immune system, which are usually in conflict with each other, to combat another resourceful adversary, the tumor,” he suggested in the announcement.
 
Likewise, at last year’s American Society of Clinical Oncology (ASCO) meeting, Amgen presented data from its Phase 1b study looking at its oncolytic herpes virus talimogene laherparepvec (T-Vec) alone or in combination with the immunotherapeutic checkpoint inhibitor ipilimumab (anti-CTLA-4) in the treatment of metastatic melanoma. Tumors shrank or became undetectable in 56 percent of patients receiving T-Vec, prior to or in combination with ipilimumab.
 
And just weeks ago, the company received a positive FDA review of T-Vec in late-stage melanoma based on Phase 3 data arising from the OPTiM study of T-Vec as a monotherapy versus GM-CSF. The approval brings the oncolytic virus one step closer to becoming only the second therapeutic onco-vaccine to be approved, after Provenge.
 
EnAd too is being tested in combination. The Octave study is looking for synergies between EnAd and paclitaxel in platinum-resistant epithelial ovarian cancer.
 
The combination possibilities are endless, but this also becomes the challenge.
 
“There are so many combinations that we can’t test all of them, and I think that’s why you see so many collaborations and deals being done at the moment on different combinations,” Beadle points out.
 
Not content to let cancer cell destruction do all the heavy lifting in immune stimulation, PsiOxus is also looking at ways to load an extra anticancer kick into EnAd, creating what it calls “armed” EnAd.
 
“You can force the cancer cells to produce non-cancer proteins,” he explains. “We could force that tumor cell to produce toxins that would kill other cells or agents that will more generally bring about the downfall of the tumor.”
 
As an example, he describes a way around the challenge of getting therapeutic antibodies into the tumor mass, a problem that plagues many programs: make the tumor cells make the antibodies.
 
“If you are producing your antibodies in the tumor in the first place, then you flip that whole problem on its head,” he says. “Instead of needing a very high systemic level of antibody to force some of it into the tumor, you actually start with the highest concentration in the tumor and you have relatively low levels in the systemic circulation.”
 
He describes the approach as “essentially gene therapy for cancer.”
 
Cellular booster shot
 
Another way to help the patient’s immune system respond to a tumor is to literally train the patient’s T cells to see the cancer by modifying them ex vivo in a process known as adoptive cell therapy (ACT).
 
In its simplest form, researchers isolate endogenous tumor-targeting T cells from patients and expand them in vitro without modification. They then reintroduce this larger population back into the patient in the hope of swamping the tumor.
 
More recently, however, researchers have performed gene therapy on the isolated T cells to introduce chimeric antigen receptors (CARs), single-chain antibodies that facilitate tumor targeting and T cell activation.
 
Although the use of autologous cells hopefully diminished the likelihood of complications such as graft-versus-host disease (GVHD), the need to modify and expand a patient’s own cells may mean increased costs and time limits on treatment. Still, that hasn’t inhibited the enthusiasm for the approach, as indicated by a number of recent moves in the industry.
 
Earlier this year, CAR specialist Kite Pharma made two announcements designed to leverage and enhance its eACT technology platform. In January, it signed a collaborative agreement with Amgen that will see the larger company open its extensive library of cancer targets to develop and commercialize next-generation CAR T cell therapies with Kite. Out of the gate, the deal pours $60 million into Kite’s coffers in upfront payments, as well as funding support for research and development through an Investigational New Drug filing.
 
Two months later, Kite took Amgen’s show of support and leveraged it into the purchase of Dutch biotech T-Cell Factory B.V. (TCF). The acquisition centers on TCF’s TCR-GENErator platform for discovering and developing tumor-specific T cell receptors (TCRs), a technology that should allow Kite to fulfill its cooperative research and development agreement with the National Cancer Institute (NCI) to develop new TCR candidates.
 
“We believe the combination of TCF’s leading technology platform, the translational and development capabilities at the Netherlands Cancer Institute and Kite’s expertise in advancing immune-oncology products will rapidly bring important TCR-based gene therapies to patients," enthused TCF co-founder Ton Schumacher in the deal’s announcement.
 
Similarly, in May, CAR specialist Juno Therapeutics announced an agreement with Fate Therapeutics that would see the two companies collaborate to identify small-molecule modulators of the genetically modified T cells. In the four-year agreement, which includes an upfront payment of $5 million and an $8-million purchase of Fate shares, Fate will be responsible for identifying and characterizing the small molecules while Juno will develop and commercialize any arising T cell immunotherapies.
 
Last year, Uruguayan researchers Nora Berois and Eduardo Osinaga discussed the use of CARs that focused on the immune-suppressive disialogangliosides GD2 and GD3 that arose from modifications in the glycobiology of neuroblastomas.
 
“A chimeric GD2-specific receptor on T-lymphocytes exhibited in-vitro anti-melanoma activity and increased survival of mice xenografted with a human melanoma cell line,” they explained in Frontiers in Oncology. “Cytotoxic T-lymphocytes (CTLs) expressing a chimeric GD2-specific receptor were generated using the Epstein-Barr virus. Infusion of these genetically modified cells (CAR-CTL anti-GD2) was associated with tumor regression or necrosis in half of the tested patients.”
 
One of the challenges of autologous T cell therapy is that many patients have already been through immune-depleting cancer therapies, and therefore may not have sufficient T cells for ACT. To address this challenge, some companies have looked at a more off-the-shelf or allogeneic approach.
 
In May, Formula Pharmaceuticals announced it had acquired worldwide exclusive rights to an allogeneic CAR platform developed at Milan’s Fondazione M. Tettamanti that relies on cytokine-induced killer (CIK) cells.
 
“CIK cells have T cell characteristics and natural killer cell properties that, within the context of CAR immunotherapy, may show efficacy and safety advantages over T cells,” explained Andrea Biondi, scientific director of Fondazione M. Tettamanti in the announcement.
 
The platform also relies on non-viral transfection to induce the genetic modification, which Formula President and CEO Maurits Geerlings suggested could make scale-up manufacturing significantly more practical and cost-effective as compared to viral transfection methods.
 
“Working with CIK cells, allogeneic blood provided by healthy donors, and non-viral transfection, we hope to provide a better alternative to patients,” Geerlings added.
 
Cell-based therapies don’t come without a cost, however, particularly on the production side.
 
“Going from small molecules to biologics and glycosylation was a layer of complication that we had to deal with,” acknowledges PCT’s Sumen. “Now we’re moving onto a very complex product with severe constraints in logistics, testing, sample volume, cost issues.”
 
Part of that crunch is handled by constant technological innovation designed to reduce the costs of goods, he suggests, but it also involves constant conversation with reimbursement agencies to redefine how you calculate the costs for any treatment, cell-based or otherwise.
 
“[We] really try to build up the concept of the total cost of treating the patient over the whole lifespan of the patient,” he explains. “That includes the cost of treatment and the cost of treatment failure.”
 
And it is the cost of repeated treatment failures that may help move these newer treatments up the clinical practice flow charts.
 
“The NCI did a very nice study where they looked at 97 Phase 1 studies with vaccines that did not have any components where there might be a risk, like having a virus in it or that sort of thing, and pointed out that there was virtually no toxicity and that it was actually wasteful to stay wedded to the classical chemotherapy paradigm where you tried to do dose-escalation studies and this type of thing,” adds Robert Dillman, vice president of oncology for Caladrius.
 
No single way
 
Another approach if you don’t have cells that specifically recognize cancer cells, according to Roche’s Umana, is to take all the T cells that are already in the body, independent of their own endogenous specificity, and redirect them to the cancer cells using something called T cell bispecific antibodies (TCBs). While one arm of the TCB binds to a surface antigen common to all T cells, the other arm tethers to the cancer cell, metaphorically rubbing the T cell’s nose in its business.
 
“The proof of concept for that approach is already available in refractory ALL [acute lymphoblastic leukemia] with blinatumomab,” he explains.
 
Last December, Amgen announced FDA approval of Blincyto (blinatumomab), its bispecific CD19-directed CD3 T-cell engager antibody. The approval also makes it the first single-agent immunotherapy directed against Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL.
 
The approval was based on results from a Phase 2 study showing that 42 percent of patients achieved complete remission or complete remission with hematologic recovery within two cycles of treatment, and of those, 75 percent achieved minimal residual disease status.
 
According to a recent review by Ulrich Weidle and colleagues at Roche and the University of Stuttgart, the concept of TCBs has been around for more than 20 years, but development was significantly slowed by an array of technical hurdles.
 
“Today, however, progress in protein design and production technologies has led to the availability of many different recombinant protein formats suitable for generation of [TCBs],” the authors wrote in Seminars in Oncology.
 
The sheer array of products currently pushing into clinical testing would seem to bear that enthusiasm out.
 
At the recent American Association for Cancer Research conference in Philadelphia, the phrase that was on everyone’s lips was “checkpoint inhibitors,” fueled by amazingly long-lasting efficacy in subsets of cancer patients.
 
For example, recent Phase 3 trials in melanoma of Bristol-Myers Squibb’s Yervoy (ipilimumab), a CTLA-4 inhibitor, showed more than 20 percent of patients living beyond four years, with a subset of patients showing survival 10 years and beyond.
 
Likewise, significant improvements in overall survival led to FDA approval of PD-1 inhibitors Keytruda (pembrolizumab) from Merck in melanoma and Opdivo (nivolumab) from Bristol-Myers Squibb in melanoma and, more recently, non-small cell lung cancer.
 
Given the success of these molecules, several other groups are looking not only at their own versions of CTLA-4 and PD-1 inhibitors, but also other checkpoint molecules such as PD-L1 (the ligand for PD-1), LAG-3 and TIM-3, as well as co-stimulatory molecules OX40 and 41BB, all in the hope of keeping the tumor from disrupting the immune response.
 
In February, for example, Roche announced the FDA had granted Breakthrough Therapy Designation for its investigational anti-PD-L1 therapeutic MPDL3280A in the treatment of non-small cell lung cancer, following up on a similar designation last year for the same molecule in metastatic bladder cancer. The designation expedites the development and review of medicines intended for serious diseases and ideally facilitates the approval process to get them to patients.
 
But as Roche’s Umana suggests, these compounds only seem to work in a portion of the patient population, and so like most other cancer treatment plans, the focus is on making rational combinations of therapies to ideally offer efficacy to a broader range of patients.
 
“The clinical application of multiple immunotherapies in combination will require careful consideration of several factors, including the timing of agent administration (concurrent vs. sequential, as previously evaluated), the potential for overlapping/additive toxicities of the individual agents and particularly the development of synergistic toxicities, including potential sequelae of immune system overstimulation,” wrote the University of Chicago’s Stefani Spranger and Thomas Gajewski in a 2013 review paper.
 
“However, with appropriate adverse-event management, treatments targeting multiple, discrete branches of tumor-associated immunity may have the potential to improve patient outcomes dramatically.”
 
“One of the studies that we are setting up to run later this year is EnAd with a checkpoint inhibitor in colorectal cancer [CRC],” offers PsiOxus’ Beadle. “CRC has been shown to be a tumor type that does not respond well to checkpoint inhibitors, but there is reason to believe that the combination of a checkpoint inhibitor and EnAd in CRC may tip the balance.”
 
And it may also be possible, using biomarker initiatives, to identify those patients who will respond best to such interventions, a direction in which Roche is investing heavily.
immuno
“We recently made a commitment to partner and collaborate with Foundation Medicine where we also expect to make moves in an area we call immunogenomics, looking for markers at the genomic level that help to predict immune responses or non-responses or inflammatory immunogenicity or not,” says Rommel.
 
“In addition to this is something called immunophenotyping, where we are trying now in biopsy material—pre-, post- and during therapy, ideally whenever available—to understand the profile of tumor cell infiltrates,” he continues. “Quantifying this is so critical but is so difficult, and it will take us a long time to figure that out.”
 
(Such efforts will be discussed in greater detail in the July DDNews Special Report Feeling Out Phenotype.)
 
Despite the challenges that remain and the clinical trials yet to be run, the various inroads being made in immuno-oncology have led to a significant shift in the mindsets of people trying to understand and treat these diseases.
 
The C-word that was “cancer” is slowly and quietly being usurped by another C-word once thought misguided and only murmured in our dreams: “cure.”
 

Why choose your target?
 
Going one step further than adoptive cell therapy (ACT), Caladrius developed a cell-based therapeutic vaccine that expands its scope while narrowing its focus.
 
According to Robert Dillman, vice president of oncology for Caladrius, rather than focus their approach on a vastly heterogeneous population of cancer cells within a tumor, the company’s vaccine program homes in on just the cells that propagate the tumor—what he calls the cancer-initiating cells or tumor stem cells.
 
“Most of what we see when we see a tumor mass are cells that are distant daughter cells of those original tumor stem cells, and those cells can undergo a few cell divisions, but eventually they die out from programmed cell death or apoptosis,” he explains. “It’s those cancer-initiating cells or tumor stem cells that really keep the tumor going. In a disease like acute leukemia, it’s been estimated that the tumor stem cells represent only maybe one out of 100,000 cells.”
 
But where the platform homes in on a particular cell, it remains broad in its selection of cancer antigens to which to tune the harvested immune cells. Rather than take what might be termed a monoclonal focus as is the case with CAR and TCR cell therapies with one molecular cancer target, Caladrius takes on all comers.
 
“We know that those tumor cells contain hundreds to thousands of non-synonymous mutations that potentially can produce patient-specific neo-antigens,” Dillman continues. “The question is how well does the immune system recognize them, and that is a complex issue.”
 
“What we’re doing is trying to markedly increase the number of those antigens without knowing what they are and then relying on the patient’s APCs to actually present them, but we’re not trying to target any specific antigens.”
 
Thus, in theory, the therapy is not neutralized by a single mutation that could knock out a single targeting mechanism. Even if such a mutation were to occur, there are enough other neo-antigens against which the cell therapy has been trained to maintain the attack on the tumor.
 
And as with other ACTs, the immune system retains the memory of the tumor such that the attack can be renewed should the cancer return.
 
At the end of April, the company announced the randomization of its first patient in a Phase 3 trial of its lead candidate NBS20, which targets advanced melanoma and was developed by Dillman before he joined Caladrius. In two Phase 2 studies, more than 70 percent of patients achieved the two-year survival endpoint and in one of the studies, median survival was five years.
 

Taking stock of the latest in the always-busy cancer landscape
 
As long as we have a Special Report on cancer, let’s wrap it up with a quick overview of some recent oncology-oriented news.
 
AbbVie completes acquisition of Pharmacyclics
 
NORTH CHICAGO, Ill.—AbbVie announced recently that it has completed the acquisition of Pharmacyclics Inc., enhancing AbbVie's scientific and commercial presence in oncology. Pharmacyclics is a leader in the hematological oncology market with Imbruvica (ibrutinib), a first-in-class BTK-inhibitor used to treat hematological cancers in what is a $24-billion global market.
 
“The companies' shared expertise, combined with AbbVie's broad late-stage oncology pipeline, has the potential to transform the cancer treatment landscape for hematological malignancies and improve patient outcomes and quality of life,” said Richard A. Gonzalez, chairman and CEO of AbbVie.  "Today marks a significant step forward in our effort to become a leader in oncology and meaningfully augment our long-term growth strategy. The Pharmacyclics team has built an important and rapidly growing franchise with significant long-term potential across a range of hematological cancers."
 
Imbruvica is approved for use in four indications in the U.S. and is the only product to have received three Breakthrough Therapy designations by the U.S. Food and Drug Administration.  As part of a worldwide partnership with Janssen Biotech, Inc., Imbruvica is now approved in nearly 50 countries. Imbruvica is in mid- and late-stage development for additional hematological oncology indications, with more than 60 clinical trials underway, including 13 in Phase 3 development. Imbruvica is also in early-stage development for solid tumors. AbbVie will market Imbruvica in the United States.
 
Across its oncology pipeline, AbbVie has five late-stage assets in clinical development positioned to launch within the next several years. Two programs—venetoclax, a Bcl-2 inhibitor, and duvelisib, a dual PI3 kinase inhibitor—are in development for hematological cancers. AbbVie intends to explore these assets in combination with Imbruvica to evaluate the potential for meaningful improvement beyond the current standard of care.
 
Pharmacyclics will be a wholly-owned subsidiary of AbbVie and will operate from its previous Sunnyvale, Calif. headquarters. Wulff-Erik von Borcke, a longtime industry leader and former head of AbbVie's global marketing, will lead Pharmacyclics as president.
 
Immunomedics reports complete responses in TNBC patients
 
CHICAGO—Immunomedics Inc. has announced that among 49 patients with metastatic triple-negative breast cancer (TNBC) evaluated for response to treatments with sacituzumab govitecan in a mid-stage clinical study, 31 percent showed a reduction in tumor size of 30 percent or more. They include two patients with complete response. Adding the patients with responses between less than 30 percent tumor shrinkage and less than 20 percent tumor increase, the disease control rate was 76 percent.
 
Sacituzumab govitecan also reportedly produced significant duration of response in these responding patients. Measured as the time it takes from the beginning of sacituzumab govitecan treatments to when the cancer progresses, the median progression-free survival (PFS) for the 48 TNBC patients who received the optimal doses of 8 or 10 mg/kg was six months. Importantly, 63 percent of patients had a time-to-progression longer than their last therapy, notwithstanding disease progression has not yet happened in 56 percent of patients at the time of analysis.
 
These results were presented at the 2015 Annual Meeting of the American Society of Clinical Oncology by Dr. Aditya Bardia of Massachusetts General Hospital Cancer Center in Boston and a faculty member at Harvard Medical School, who commented, “Given that a majority of the patients enrolled into this study had failed four or more prior cancer therapies, some as many as 11, we are quite encouraged with sacituzumab govitecan in this late-stage setting in an aggressive disease that is difficult to treat.”
 
Entolimod holds potential for many solid tumors
 
BUFFALO, N.Y.—A collaborative team of researchers led by Dr. Alex A. Adjei of Roswell Park Cancer Institute shared results from the first clinical study of the anticancer effects of the novel agent entolimod at the American Society of Clinical Oncology’s 51st Annual Meeting in Chicago. Their findings confirmed preclinical evidence that the agent, which is derived from Salmonella flagellin, is worthy of further investigation as treatment for some of the most common and most resilient solid-tumor cancers.
 
The researchers noted that among 26 participants in this dose-escalation study, eight patients had stable disease for more than six weeks following treatment with entolimod, and three patients maintained disease stability for longer than 12 weeks. The tolerability profile in patients with advanced cancer was similar to that observed in two previous studies in 150 healthy volunteers who received entolimod in a similar dose range. Mild-to-severe but manageable side effects such as hypotension and hyperglycemia, all of them anticipated effects of TLR5 activation, were observed in several patients. The results corroborated preclinical findings and suggest that entolimod should be further studied as an immunotherapeutic anticancer agent.
 
“Our findings are encouraging, as they suggest that entolimod can be safely combined with other chemotherapeutic, targeted or immunotherapeutic agents as treatment for advanced and very hard-to-treat cancers,” notes Adjei, who is senior vice president of clinical research and the Katherine Anne Gioia Chair in Cancer Medicine at Roswell Park. “We’ve identified a recommended dosing schedule for future studies.” 
 


Subscribe to Newsletter
Subscribe to our eNewsletters

Stay connected with all of the latest from Drug Discovery News.

September 2024 front cover

Latest Issue  

• Volume 20 • Issue 5 • September 2024

September 2024

September 2024 Issue