Nanotech Remains a Robust Research Focus

Ennio Tasciotti, PhD

Despite several high-profile setbacks in recent years, efforts to transform cancer care by using nanotechnology to deliver medications directly into patients’ tumors are moving forward, with the FDA’s ongoing review of a novel formulation generating fresh excitement in the field.

CPX-351 (Vyxeos), the first nanotechology drug to combine 2 medications in the same delivery vehicle, is being evaluated under the FDA’s priority review program after producing positive results in a phase III trial against secondary acute myeloid leukemia (AML).¹ The drug, which the FDA also has designated a breakthrough therapy, demonstrated a 31% reduction in the risk of death compared with standard chemotherapy in older patients (ages 60-75) with high-risk AML.

Overall, the FDA has approved 6 anticancer therapies that nanotechnology since the first such drugs were cleared for the US market in the 1990s (Table).² At least 4 other nanotherapeutics are approved in other countries, and more than 2 dozen novel therapies are under study in clinical trials.²

Experts say the fundamental theory that underlies the use of nanotechnology in drug delivery remains compelling and that a greater understanding of tumor biology will improve the prospects for its use in oncology in the future.

“Progress in nanotechnology has gone faster so far than it did with either biologic treatments or immunotherapies. We have learned so much about making nanoparticles, and we are now discovering how they really work in the body and how they interact with cells and tissues,” said Ennio Tasciotti, PhD, co-chair of the Department of Nanomedicine at The Methodist Hospital Research Institute in Houston, in an interview with OncologyLive^®. “This line of attack will greatly improve cancer care at some point. It’s just a matter of time.”

The term “nanotechnology” applies to any designed and manufactured object that measures 1 to 100 nm.3 The nanoparticles currently used to deliver cancer medications generally measure 30 to 100 nm. That may sound too small for drug delivery when you consider that a sheet of paper is about 100,000 nm thick⁴, but there is plenty of space for medicinal cargo. A 100-nm particle dwarfs a chemotherapy molecule to the degree that the Goodyear Blimp dwarfs a soccer ball (Figure).⁵

Chemotherapy molecules, which are the payload in most therapeutic nanoparticles to undergo latestage trials so far, are so small that they leak out of every blood vessel and poison the entire body. Nanoparticle delivery vehicles, on the other hand, are intentionally designed so that they should be too large to escape from healthy blood vessels, yet small enough to escape many of the hastily built (and therefore somewhat leaky) blood vessels that feed rapidly growing tumors.⁶

Table. FDA-Approved Oncology Nanotherapeutics

Size was the main advantage of first-generation nanoparticles, which were simple lipid vesicles coated with polyethylene glycol (PEG) to prevent an immune response. Subsequent designs have used particular shapes and ligand coatings to better target tumors, as well as timed chemotherapy release to increase exposure times and encourage the accumulation of medication on tumor tissue. The goal was simple: getting far more medication to tumor cells while virtually eliminating contact between chemotherapy and healthy tissue.⁷

ALL indicates acute lymphoblastic leukemia; HCI, hydrochloride; NSCLC, non—small cell lung cancer.

Disappointing Findings

Intuitively, this approach seems like a surefire strategy. However, clinical trial results have often not lived up to expectations. Many nanoparticle formulations that have undergone late-stage cancer trials have demonstrated no therapeutic advantage over standard therapies; several high-profile developments illustrate this trend.

NK105, a paclitaxel-infused nanoparticle, failed to increase overall survival (OS) in a phase III trial that compared the novel drug with standard paclitaxel in patients with metastatic or recurring breast cancer, Nippon Kayaku, the Japanese company developing the drug, reported in July 2016.⁸ The nanoparticles used in the experimental formulation were designed both to deliver the medication directly to tumors and to control the timing of its release so as to increase the contact period between paclitaxel and tumor from 30 minutes to 10 hours.

CRLX101, a camptothecin-carrying nanoparticle, failed to outperform standard therapy when combined with bevacizumab in a phase II study in patients with previously treated renal cell carcinoma, according to the drug’s developer, Cerulean Pharma.⁹ Median progression-free survival (PFS) was 3.7 months among patients receiving the experimental treatment and 3.9 months among patients receiving standard care. The objective response rate (ORR) was 5% among patients with the study drug compared with 14% among patients in the control arm.

Another major disappointment was the failure of an entire company that once ranked among the most highly regarded creators of nanotechnology in the world. Bind Therapeutics used technology developed at Harvard University and MIT for the systematic design of next-generation nanoparticles that theoretically could target any type of cell.

With no real-world validation beyond the results of a single phase I trial, Bind signed a trio of deals with major pharmaceutical companies that were reportedly worth up to $200 million. The company launched several trials of its lead compound BIND— 014, a polymeric nanoparticle that contained docetaxel targeted to prostate-Ennio Tasciotti, PhD specific membrane antigen, which produced disappointing results. Last year, the company filed for bankruptcy protection and the bulk of its assets were sold to Pfizer for $40 million.¹⁰

The precise explanation for these failures is unclear and likely varies from compound to compound, but researchers who specialize in nanotechnology have identified a handful of potential problems. Nanoparticles can be made in a wide variety of shapes that each act differently in the body—rods, branches, flowers, snowflakes, dendrites, chains, and more—and many makers of failed nanoparticles may have chosen a suboptimal shape.¹¹ Individual patient tumors, moreover, seem to vary enough that a single nanoparticle design would not work for a majority of patients. Whatever the cause, analysis suggests that most nanoparticle drug formulations fail because they do not cause significantly more chemotherapy accumulation at tumor sites than do regular infusions.²

Even nanoparticles that have won FDA approval have sometimes struggled to demonstrate a therapeutic advantage over control treatments in late stage trials. Doxil, which encapsulates tiny doxorubicin molecules inside lipid bubbles and PEG, produced slightly inferior PFS (6.9 vs 7.8 months) and OS (21 vs 22 months) than standard doxorubicin during a phase III trial involving 509 women with untreated metastatic breast cancer.¹² The drug’s approval, and its subsequent growth to $600 million in annual sales, hinged largely on significant reductions in toxicity.

Tasciotti is among the researchers who take these disappointments in stride. “The failure of individual drug candidates does not necessarily invalidate an entire strategy. A full 20 years elapsed between the discoveries that got people excited about monoclonal antibodies and the string of approvals that really started transforming cancer care. Immunotherapy has taken even longer to mature,” he said. “Researchers spent half a century trying to get the immune system to fight cancer before they achieved the breakthroughs we’ve seen in the past 5 years.”

Successes in the Field

In this challenging drug development landscape, nab-paclitaxel (Abraxane) has emerged as a strong nanotherapeutic entry. The drug has been approved for the treatment of patients with metastatic breast cancer after the failure of prior chemotherapy, as first-line therapy in locally advanced or metastatic non—small cell lung cancer (NSCLC) in combination with carboplatin, and as frontline therapy in metastatic pancreatic adenocarcinoma in combination with gemcitabine.

The breast cancer approval was based upon a significant improvement in the response rate in target lesions with nab-paclitaxel compared with paclitaxel (21.5% vs 11.1%; P = .003).

In NSCLC, the ORR with a nab-paclitaxel/carboplatin combination was 33% across histologies compared with 25% for paclitaxel/carboplatin in the pivotal clinical trial that led to its approval in that indication (P = .005).13 In the squamous cell NSCLC subgroup, the ORR rose to 41% with nab-paclitaxel.

In metastatic pancreatic cancer, there was a clear improvement in OS in the pivotal phase III MPACT trial: the combination of nab-paclitaxel plus gemcitabine resulted in a median OS of 8.5 months compared with 6.7 months for gemcitabine alone (HR, 0.72; 95% CI, 0.62-0.83; P <.0001).¹³

Nab-paclitaxel combines chemotherapy with human serum albumin molecules that have 2 functions: they eliminate the needs for the toxic solvent used to combat the hydrophobia of standard paclitaxel and for infusion systems or steroidantihistamine premedications to keep standard paclitaxel from binding to itself and obstructing capillaries.

Strong Results for CPX-351

Another nanotherapeutic that has improved outcomes in pancreatic cancer is ironotecan liposome injection (Onivyde; MM-398). In the phase III NAPOLI-1 trial, the addition of MM-398 5-fluorouracil (5-FU) and leucovorin in patients with metastatic disease following prior gemcitabine- based therapy demonstrated a 1.9-month improvement in OS. In the combination arm, the median OS was 6.1 months compared with 4.2 months with 5-FU and leucovorin (HR, 0.68; log-rank P = .014).¹⁴ For many patients, the benefits lasted longer—the 1-year survival rates were 26% versus 16%—but survival rates at 20 months were similar.¹⁴ The FDA approved MM-398 in October 2015.Thus far, researchers have been impressed with clinical trial results for CPX-351, which is nanoscale liposome co-formulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio.

The new drug application for the compound includes clinical data from 5 studies, including findings from the pivotal phase III study comparing the formulation with cytarabine and daunorubicin (7+3), according to Jazz Pharmaceuticals, the company currently developing the drug. Phase III results showed that CPX-351 reduced the risk of death by 31% compared with 7+3 for older patients with high-risk, secondary AML. The formulation showed a median OS of 9.56 months (95% CI, 6.60- 11.86) versus 5.95 months (95% CI, 4.99-7.75) with 7+3 (HR, 0.69; P = .005).¹⁵

OS was 41.5% at 12 months and 31.1% at 24 months with CPX-351 compared with 27.6% and 12.3%, respectively, for standard therapy. Toxicity and adverse events were similar for patients in both groups.¹⁵

Principal investigator Jeffrey E. Lancet, MD, senior member and chief of the Leukemia/Myelodysplasia Program at Moffitt Cancer Center, said the formulation, “should be considered standard first-line treatment for older patients with high-risk AML” when presenting findings during the 2016 American Society of Clinical Oncology Annual Meeting.

Future Directions

“This particular formulation is very exciting because it is the first to pack 2 therapeutic agents into a single delivery vessel and because the vessel is cleverly designed to deliver those 2 agents in a very precise ratio over time in a way that would be nearly impossible using infusions,” said Piotr Grodzinski, PhD, director of the National Cancer Institute’s Office of Cancer Nanotechnology Research.In analyzing the recent pattern of nanotechnology trial findings, Grodzinski believes, in retrospect, that researchers were overly optimistic about the results they were likely to attain simply by packing commonly used chemotherapies into nanoparticles.

“Was it reasonable to expect significantly better results with exactly the same therapeutic agents? Possibly, but only if tumors consistently received dramatically more chemotherapy via nanoparticle delivery than they receive via normal infusions,” Grodzinski said. “The effectiveness of nanoparticle delivery will vary among different tumor types and will also be heterogenous from patient to patient. Details of delivery mechanisms need to be further studied to improve their effectiveness. Our NCI funding programs put emphasis on such studies, in addition to an overall push for the translation of medical nanotechnologies.”

Researchers now are looking at several ways to increase the efficacy of nanoparticle medications. Some are looking for tests that will indicate which patients will have the type of tumors that experience chemotherapy accumulation with the current style of nanoparticle. Others are looking to use nanoparticles to deliver medications that are too toxic for conventional infusions but may be more effective because of that toxicity. Still others are seeking to use nanoparticles to deliver antibodies, immunotherapy, or combinations of several treatment types.

The first line of inquiry, looking for tests that will predict who will respond to nanoparticle delivery of particular chemotherapies, stems from the observation that tumor permeability and chemotherapy retention vary greatly among patients with the “same” kind of tumor. Several nanoparticle formulations that have failed to significantly increase average chemotherapy accumulation across an entire trial cohort have managed to increase it greatly in a relatively small percentage of trial patients. If such patients could be identified beforehand, today’s “failed” nanoparticles could prove a godsend to a significant minority of patients.

Merrimack Pharmaceuticals, for example, undertook several studies to see whether magnetic resonance imaging with an iron oxide nanoparticle could help predict the intratumoral uptake and activity of MM-398 in individual patients. Preclinical results were very promising,¹⁶ so the company decided to launch a pilot study, which was taken over by Ipsen after that company bought Merrimack’s oncology business.¹⁷

Another idea for improving results is to move away from synthetic designs to formulations that mimic cells that already move through the body and interact with drug targets, such as complex cells like exosomes that, according to Tasciotti, “have been optimized by the millions of years of R&D known as evolution” to move through the body. Tasciotti’s team has been testing such particles in animals, and the results are promising.¹⁸

The concept of using nanoparticles to deliver potentially effective medications that had been abandoned because they were too toxic for conventional delivery is another hypothesis being studied. Researchers have tested a number of ideas and enjoyed some early successes. A team from the University of North Carolina at Chapel Hill, for example, developed a nanoparticle formulation of wortmannin, a highly potent radiosensitizer that was abandoned because of toxicity.

Preliminary research demonstrated that the nanoparticle formulation of wortmannin was less toxic in vivo and in vitro than the conventional formulation but that it remained a better radiosensitizer than cisplatin.¹⁹ That said, neither the nanoparticle version of wortmannin nor a nanoparticle version of any other medication previously abandoned for excessive toxicity seems to be in late stage trials at present.

Nanoparticle formulations of biologic medications and immunotherapies are also in early stages of development at present, and several research teams around the world are pushing them forward.

Researchers from Mayo Clinic, for example, have developed a nanoparticle designed to stimulate the body’s immune system to target breast cancer. The experimental treatment is coated both with antibodies designed to make it bind to HER2 molecules and with molecules designed to stimulate an immune response. The team has published several reports on its progress, including encouraging results in mice, most recently in Nature Technology.²⁰

“There are many advantages of delivering immunotherapies using nanomedicine,” said team leader Betty Y.S. Kim, MD, PhD, an assistant professor of cancer biology, neuroscience, and neurosurgery at Mayo in Jacksonville, Florida.

“Because of their synthetic nature, nanomaterials have the tendency to be more efficiently detected by certain immune cells. This makes them more efficient as delivery devices to target those cells. Also, some of the immunotherapies currently being investigated such as DNA or RNA to program immune cells are prone to degradation within the body. By encapsulating these molecules inside a nanomaterial core, it can prevent the molecules from being degraded before they reach their intended target. Finally, nanomedicine enables multiple agents to be delivered to a target at the same time.”

References

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