Small Molecule Chemotherapy

Wuxi AppTec: Small Molecule Chemotherapy May Play a Big Role in Cancer Immunotherapy

The combination of chemotherapies and immunotherapies highlights the significance of small molecule drug development as an ongoing treatment modality. Although there has been an explosion in immunotherapy development, small molecules continue to dominate the treatment of cancers, and recent research reveals that chemotherapies, such as taxanes, benefit immunotherapies.

The validity of combining traditional cancer chemotherapy with new immunotherapies received a major boost recently when Merck and Roche released positive findings from lung cancer clinical trials involving chemotherapy in combination with their respective checkpoint inhibitors, Keytruda (pembrolizumab) and Tecentriq (atezolizumab).

“Immunotherapy certainly represents a significant advance in cancer treatment,” says NanOlogy™ CEO Paul Dorman. “But many experts agree that combining traditional chemotherapy and immunotherapy – or chemoimmunotherapy as we call it – may benefit a greater number of patients with lung and other cancers.”

The rationale is based on recent research that has shown chemotherapy, which was once thought to be only immunosuppressive because of bone marrow suppression, is also immunogenic through its tumor killing effect. These counteracting properties partly account for why systemic administration tends to be only modestly immunogenic. Nevertheless, much oncology clinical research is in process with different combinations of chemotherapy and immunotherapy.

NanOlogy entered the emerging chemoimmunotherapy field from the chemotherapy side with unique forms of submicron particle paclitaxel, called NanoPac™, and submicron particle docetaxel, called NanoDoce™, which are designed for concentrated, sustained delivery directly to tumor sites rather than systemwide administration via intravenous infusion.

Preclinical and clinical data generated on NanoPac and NanoDoce are providing evidence that concentrated, sustained local delivery, via inhalation or intratumoral injection for example, leads to a greater tumor response without the side effects of systemically administered drug. Importantly, the investigational drugs appear to be eliciting a stronger immune response than their systemic counterparts.

As Dorman explains, “We are showing that local delivery of certain chemotherapeutic agents has the potential to improve their cancer killing properties and immunogenic effects without producing the toxic side effects of systemic administration.”

Dorman founded NanOlogy in 2015 after acquiring exclusive worldwide rights to a proprietary submicron particle production technology that could give chemotherapy renewed respect as a cancer treatment. For NSCLC, the company has developed a form of NanoPac designed for nebulized inhalation directly into the lungs.

“Lung cancer kills more people worldwide than any other cancer,” Dorman observes. “In China alone, it is responsible for more than 700,000 deaths annually. Based on our recent preclinical experience, we believe inhaled NanoPac may offer a better option than systemic chemotherapies in combination with immunotherapy for treating lung cancer.”

WuXi AppTec Communications recently talked with Dorman about the benefits of combining the new immunotherapies with traditional chemotherapies and his company’s unique approach.

WuXi: How was NanOlogy formed?

Paul Dorman:  NanOlogy was started in 2015 by DFB Pharmaceuticals, a private Texas-based investment and development company I founded in 1990 with two partners.

DFB grew through acquisitions and startups of pharmaceutical related businesses and products and ultimately sold several major operating companies in 2012 realizing significant value. We kept one of our companies, Phyton Biotech, to increase our foothold in oncology.

In addition, we increased our efforts to discover new opportunities in and around oncology. This led to the identification of an innovative submicron particle manufacturing technology developed by a company called CritiTech.

We formed NanOlogy together with CritiTech and in collaboration with US Biotest, which manages our preclinical and clinical activities. The collaboration has leveraged the unique capabilities of our three companies and has allowed us to expand the technology into multiple products and therapeutic areas.

WuXi: Why combine immunotherapies with traditional chemotherapies?

Paul Dorman: The first generation of immunotherapy drugs, such as the checkpoint inhibitors, represent a remarkable breakthrough in cancer treatment. But less than 30% of patients respond to checkpoint inhibitors and the drugs are not effective against all cancers.

When paclitaxel was introduced in the 1990s it was considered a game changer in the treatment of cancer because of how it works. The drug prevents cell division causing cell death, and its effect is much greater on rapidly dividing cells, like cancer cells, making it useful against a broad range of cancers.

The realization that chemotherapy agents like paclitaxel can have an immunogenic effect make them an attractive partner for immunotherapy. More than 170 clinical trials worldwide are in process with chemotherapy agents and checkpoint inhibitors alone to identify new and better ways to combine these agents.

Unfortunately, chemotherapy drugs do not discriminate between cancer cells and healthy cells, so systemwide administration can lead to serious systemic side effects. Additionally, these side effects are additive to toxicity of immunotherapy making it difficult to optimize their use together.

NanOlogy investigational drugs are intended to enhance tumor kill, elicit a greater immune response, and not contribute to systemic side effects – all because they are locally delivered as particles in high concentration where they become entrapped at the disease site releasing drug over a long time.

WuXi: Most chemotherapies are small molecules. With all the recent attention of academia and the news media on immunotherapies, what role will small molecules play in the future?

Paul Dorman:  Small molecules continue to dominate drug approvals and drug development in general. They constitute a broadly diverse group of therapeutic agents, and, as we have seen in treatment of cancer, they will play a key role as combination products with immunotherapeutic and other therapies.

But small molecules also have advantages over immunotherapies in that they are generally much easier to make and much less expensive to manufacture on a commercial scale. Also, advances in genomics have identified many more specific genetic targets in disease pathways that can be disrupted with small molecule drugs as well as biologics.

Our technology also provides a great example of how delivery of existing small molecules can be significantly enhanced and their therapeutic activity improved. Because paclitaxel is poorly soluble in physiologic fluids, solvents or coating agents must be added to solubilize the drug in the body, so it can be infused systemically to reach the disease site. Unfortunately, many solvents are toxic and add to the drug’s side effects.

Because of NanOlogy’s manufacturing technology, our submicron particles require no solvents or coating agents, so we can deliver pure drug particles directly to the site of the cancer, and for the first time take full advantage of the drug’s cancer killing ability, while minimizing systemic toxicity at the same time.

WuXi: Why are chemotherapy and immunotherapy synergistic when combined?

Paul Dorman: Immunotherapy checkpoint inhibitors like Keytruda, for example, are monoclonal antibodies that block a cancer cell’s ability to hide from the immune system. Once the cancer cells are exposed to the immune system, the immune system can attack and destroy them. Systemic chemotherapies are known to generate a modest immune response and that in turn stimulates the immune system to help an immunotherapy drug like Keytruda.

What we have found in our preclinical lung cancer studies is that when NanoPac is inhaled into the lungs, the local concentration and sustained release over time significantly increases tumor kill relative to systemic administration of paclitaxel. We have seen this same effect with NanoPac and NanoDoce in other tumor types as well. The enhanced kill results in greater exposure of tumor specific antigens, which elicits a stronger immune response. It stands to reason a stronger immune response will offer a greater benefit to immunotherapies.

WuXi: How is NanoPac made and how is it different from regular paclitaxel?

Paul Dorman: Intravenously administered paclitaxel is indicated for non-small cell lung cancer (NSCLC) and is one of the key agents prescribed for lung cancer. NanoPac is different because it is a novel targeted therapy made up of submicron particles of pure paclitaxel designed for nebulized inhalation. The particles of pure drug are stable in powder form without the need for coating or carrier agents.

They are formed by a proprietary manufacturing process that uses supercritical fluid carbon dioxide and sonic energy to reduce paclitaxel crystals into submicron particles without imparting static charge to the particles. So, the particles remain free flowing and stable in powder form and are simply suspended in a saline-based nebulization fluid prior to inhalation.

The particles are so unique in terms of size and shape, they have been granted a composition of matter patent in the US that is valid until 2036. Size, surface area, density, and dissolution are all protected by the patent and form our proposed regulatory specifications. This gives us new molecular entity like IP protection on NanoPac and that’s a big deal. We’ve now built an extensive patent portfolio that has been filed in China, US, Europe, Japan, and other major countries.

WuXi: What were the preclinical studies in lung cancer and what were the results?

Paul Dorman: We first did a rat inhalation pharmacokinetic study where NanoPac was successfully delivered to the lungs via nebulization without adverse effects. We found measurable amounts of drug in lung for greater than 14 days while the IV comparator, nab-paclitaxel, was gone in a couple of days. The 14-day retention of NanoPac was a surprise to the researchers performing this well-established study as they had simply never seen this length of drug retention in lung tissue.

Next, we conducted an orthotopic NSCLC study in rats where NanoPac demonstrated significantly more tumor regression and primitive tumor cell reduction than intravenously administered nab-paclitaxel. In some cases, histopathology review of the tumors showed a complete response in NanoPac-treated animals. As with the pharmacokinetic study, no adverse effects were seen with inhalation of NanoPac in this study. We presented these results at ASCO in June.

What really excited us, however, was that we saw substantial immune cell infiltration in and around dead and dying tumor tissue upon histologic exam of lung tissue. We did not see this kind of response in nab-paclitaxel or control animals.

We then conducted immunohistochemistry which showed presence of several types of cancer-killing immune cells indicating the cancer killing effect of NanoPac may result from both a drug-mediated tumor kill and an immune cell-mediated tumor kill. We’ve now seen similar immune responses with local delivery of our particles in breast, renal, and bladder tumors in animals, and prostate tumors in humans.

Our rationale for this effect is that large, sustained concentration of drug at the disease site significantly increases tumor kill and local accumulation of dead tumor cell debris. This debris exposes tumor specific antigens, which elicit a strong immune response. Because of this response and lack of systemic side effects, we believe NanoPac may be the ideal drug in combination with immunotherapy agents like Keytruda or Tecentriq for certain cancers and we are conducting further research to confirm this.

WuXi: What is your strategy for developing NanoPac in combination with immunotherapy for lung cancer?

Paul Dorman: We are advancing clinical trials in the US for local delivery of our investigational drugs in three broad therapeutic areas including gastrointestinal cancers, urological cancers, and lung cancer. We intend to progress our drugs through first-in-human clinical trials and then identify a leading oncology company to advance the products through pivotal trials, regulatory approval, and to patients in need.

For lung cancer, we think the compelling preclinical data and significant patient need require us to seek out a partner sooner. We are very interested in identifying a leading oncology company in China to help bring the product to regulatory approval in China in parallel with our efforts in the United States. We are planning to begin a formal process later this year to identify a partner in China.

WuXi: Is paclitaxel more effective in combination with immunotherapies than other forms of chemotherapy? If so, why?

Paul Dorman: Taxanes like paclitaxel and docetaxel are effective for a broad range of solid tumors and because of that we selected them as the first drugs to develop. However, what I believe is more important is the ability of our technology to place large amounts of drug at the disease site releasing drug around the clock for weeks. Contrast that with systemic administration, which only allows for drug at the disease site for a few hours with each dose, and each dose must be spaced a week or more apart.

WuXi: What other cancers are you targeting? Would you pursue combination with immunotherapy for those cancers?

Paul Dorman:  Right now, we are pursuing nine indications with our investigational drugs. In addition to our preclinical work in NSCLC, we have clinical trials underway in prostate cancer, pancreatic cancer, and pancreatic cysts via intratumoral or intracystic injection.

We also have a trial completed and another underway for peritoneal cancers, where we deliver our drug directly into the peritoneum. We also have a topical form of the product that has completed a clinical trial in actinic keratosis under another DFB company called Soria and a trial underway in cutaneous metastases.

We are planning a clinical trial in bladder cancer later this year via resected bladder tumor bed injection followed by bladder instillation and in renal cancer in 2019 via intratumoral injection.

In every case, we are seeking to deliver large, sustained amounts of drug directly to the disease site with the goal of increasing efficacy, eliciting a strong immune response, and minimizing systemic side effects. So far, the data are supporting this goal and suggest our products would benefit immunotherapy.