January 1, 1970 (Vol. , No. )
Punit Dhillon OncoSec Medical
Delivering efficient drugs into cancer cells in a manner that is safe and effective is still a challenge.
The majority of all cancers are caused by solid tumors that grow as a mass of cells in a particular organ, tissue, or gland. The most common sites for these tumors are the breast, lung, prostate, colon, brain, uterus, pancreas, skin, and liver. Unfortunately, the treatment of solid tumor cancers, particularly those that have progressed to an advanced metastatic stage, continues to challenge the medical community. Despite innovations in genomics and proteomics, the development of safe and effective drug delivery mechanisms while achieving the desired treatment benefit remains unmet.
A myriad of causes lie behind the onset of solid tumor cancers. For example, the link between sun exposure and skin cancer has been studied extensively. One in five people will suffer from skin cancer at some point in their lives, and the numbers are steadily increasing. Despite advances in sunscreen technology and public awareness of the need for sunscreen, there has been an increase in the average U.S. lifetime risk of one type of skin cancer—invasive melanoma—from 1/600 in 1960 to 1/50 in 2008.
The treatment of solid tumors remains an outstanding obstacle for the healthcare community. In spite of all of the breakthroughs in drug discovery and development, it is still a challenge to transport efficient drugs into cancer cells in a manner that is safe and effective. At the same time, current therapeutic approaches involving surgery, radiation therapy, and chemotherapy each have specific and notable disadvantages.
Research and Clinical Directions
A survey of the current literature reveals that researchers are pursuing several broad approaches to solid tumor treatment. One of these involves local-only therapies such as cryotherapy, radiation, and ablation. Cryotherapy is the local or general use of low temperatures to treat a variety of benign and malignant lesions. Specifically, its goal is to decrease cellular metabolism, increase cellular survival, decrease inflammation, decrease pain and spasm, promote vasoconstriction, and, when using extreme temperatures, to destroy cells by crystallizing the cytosol. The benefits of radiation therapy have been extensively well-studied, as well as its principal drawback: It kills healthy cells alongside tumor cells. Ablation, broadly speaking, involves the removal of a part of biological tissue; techniques such as surface ablation of the skin (dermabrasion) can be carried out by chemicals or by lasers.
A second broad approach concerns therapies that can be applied either locally or distally. For example, immunotherapy stimulates the patient’s immune system to attack malignant tumor cells. This can be done through immunization of the patient (e.g., by administering a cancer vaccine), in which case the patient’s own immune system is trained to recognize tumor cells as targets to be destroyed, or through the administration of therapeutic antibodies as drugs, in which case the patient’s immune system is recruited to destroy tumor cells by the therapeutic antibodies. Another example involves stem cell transplants. Very high doses of chemo can be used (often along with radiation therapy) to try to destroy the cancer, a treatment that also kills the stem cells in bone marrow. Soon after treatment, stem cells are given to replace those that were destroyed. They are inserted into a vein, much like a blood transfusion, and over time they settle in the bone marrow and begin to grow and make healthy blood cells. This process is called engraftment.
A third area of research is devoted to pursuing a greater understanding of resistance to cancer drugs and the underlying causes of cancer recurrence. Insight from this area is bound to inform the search for more effective therapies.
Importance of Delivery and Accessibility for Solid Tumor Treatment
The efforts to streamline the techniques involved in delivering cancer drugs into solid tumors have run along several lines. Among the leading candidates are improved approaches to radiation, cryotherapy, and ablation techniques.
For example, stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy, offers a successful clinical model for the development and widespread use of new radiation therapy technologies. Early research has shown increased rates of tumor control and even survival compared to conventional radiation therapy. That said, broad acceptance of SBRT by radiation oncologists has been hampered by concerns of toxicity from the very potent, focused beams of radiation delivered to extracranial tumors using one or more dose intervals, or fractions. However, many patients prefer this short treatment course—consisting of five or fewer outpatient sessions of less than 30–60 minutes each—over conventional radiation therapy, which requires six to eight weeks of daily treatments at much lower doses. Based on patient demand and early research that has shown increased rates of tumor control and even survival compared to conventional radiation therapy, SBRT is emerging as a standard of care for treating lung, liver, and spine tumors for many medically inoperable and surgically unapproachable cancer patients. SBRT is now being investigated for the treatment of primary tumors of the breast, prostate, pancreas, and kidney, and cancers that have metastasized to the bone and lymph nodes.
Meanwhile, cryotherapy is the use of extreme cold produced by liquid nitrogen (or argon gas) to destroy abnormal tissue. Cryosurgery can be used to treat external tumors, such as those on the skin. For external tumors, liquid nitrogen is applied directly to the cancer cells with a cotton swab or spraying device. Cryosurgery is also used to treat tumors inside the body (internal tumors and tumors in the bone). For internal tumors, liquid nitrogen or argon gas is circulated through a hollow instrument called a cryoprobe, which is placed in contact with the tumor.
Alternatively, other forms of tumor ablation might be used to treat solid tumors, such as a process involving destroying the tumor inside the body. Radioactive pellets, less than an inch in length and approximately the width of a pin, can be placed inside a tumor; afterwards, the pellet emits lethal radioactive atoms that irradiate the tumor from the inside out. As the tumor disintegrates, it starts to release antigens that trigger an immune response against the cancer cells. In some cases, the body also forms an immune memory against the recurrence of tumor cells. Another proposed ablation technique, “pulsed electric current ablation,” involves the insertion of electrodes into tumors, which then release extremely high-energy electrical currents. These currents create a physical reaction that eliminates the tumor cells.
At the same time, several innovative options exist for delivering drugs into tumors. These include emulsification, nanoparticles, liposomes, microspheres, micelles, and electroporation.
Anticancer agents are typically hydrophobic and unstable in water, making formulation development a major undertaking. For this reason emulsification, the semihomogeneous mixture of two immiscible liquids, is an attractive dosage form for anticancer drugs. Research continues on the development of injectable emulsion formulations, particularly those containing anticancer drugs; the major challenges to date have involved processing difficulties, the lack of physiologically safe ingredients, and thermodynamic instability of the emulsion system.
Numerous investigations have shown that both tissue and cell distribution profiles of anticancer drugs can be controlled by their entrapment in submicronic colloidal systems (nanoparticles). The rationale behind this approach is to increase antitumor efficacy, while reducing systemic side effects. Nanoparticles are also of benefit for the selective delivery of oligonucleotides to tumor cells. Moreover, certain types of nanoparticles have showed some interesting capacity to reverse multiple-drug resistance, which is a major problem in chemotherapy.
Meanwhile, liposome-based chemotherapeutics used in the treatment of tumors can in principle enhance the therapeutic index of otherwise unencapsulated anticancer drugs. This is partially attributed to the fact that encapsulation of cytotoxic agents within liposomes allows for increased concentrations of the drug to be delivered to the tumor site. In addition, the presence of the phospholipid bilayer prevents the encapsulated active form of the drug from being broken down in the body prior to reaching tumor tissue and also serves to minimize exposure of the drug to healthy sensitive tissue.
Microsphere technology is another recent trend in cancer therapy. Radioactive polymer spheres can be designed to emit beta radiation. Physicians insert a catheter and can deliver millions of the microspheres directly to the tumor site. Microsphere technology is a promising method that can be used for site-specific action without causing significant side effects in normal cells.
Polymeric micelles are also used as drug delivery vehicles. They are prepared from certain amphiphilic co-polymers consisting of both hydrophilic and hydrophobic monomer units. They can be used to carry drugs that have poor solubility. Techniques have been developed that utilize reactive polymers along with a hydrophobic additive to produce a larger micelle, which creates a range of sizes.
Another promising approach to treating solid tumors targets the tumor itself without affecting any of the surrounding healthy tissue, ensuring that a drug or other therapeutic agent is immediately absorbed by the cancer cells. One such targeted therapy could harness a scientific phenomenon known as electroporation. Derived from the words “electric” and “pore,” this involves applying a brief electric field to a living cell. Doing this causes a temporary opening of pores in a cells membrane—pores that close again within minutes once the electric field is discontinued. By creating these membrane pores, the cell’s permeability is temporarily increased, and a drug or other agent injected into the area can flow into the cell by an increased factor of 1,000 or more. An apparatus could be constructed consisting of a generator that creates a pulsed electric field and using a handheld applicator with electrode needles at its tip; the cancer cells affected by this electric field would undergo electroporation.
Such technology has been conceived for use in two separate kinds of therapy: electrochemotherapy and electroimmunotherapy. In the former, an anticancer drug could be injected into a tumor that is electroporated; consequently, the quantity of drug required would be well below that needed in traditional chemotherapy. Meanwhile, the latter therapy would involve the use of a specific cytokine, a substance known to boost the human immune system against cancer cells, to stimulate an immune response producing both a local and a systemic effect against cancerous cells.
The Business of Developing Solid Tumor Therapies
The year 2013 has been an impressive one for advancements in solid tumor research. At Tufts University, biologists harnessed bioelectric cancer detection, which assumes tumor sites exhibit a distinct voltage or bioelectric signal compared to surrounding cells. At the University of Washington, researchers used minute coloring material to pinpoint proteins in cancer cells, analyze cells unaffected by treatment, and attempt to predict which cells may become cancerous and why.
Leaders of companies developing cutting-edge treatments for solid tumors ought to be especially attuned to the benefits that can accrue from relationships with academia, especially the access such relationships offer to facilities and researchers. Academic institutions represent a central partner for the biotech industry that allows for an ever-growing synergy of discovery and commercialization.
University collaboration has not only resulted in creating unique opportunities—such as the initiation of clinical trials for the current clinical indications in development pipelines—but also provided guidance for the direction of new technology and product development.
From a business standpoint, the relationships that allow academic institutions to provide a research outcome are only one of the components of importance. The importance of university collaboration lies not only in the outcome but also in the impact—i.e., how the new knowledge derived from a collaboration with a university can contribute to future efforts and, ultimately, a company’s performance. Companies should constantly strive to answer the following questions in their evaluation of academic collaborations. Are new therapeutic product opportunities made possible? New and more effective treatment processes? Novel innovations and optimization of a delivery platform? Intellectual property, clinical know-how, or processes that enhance competitive advantage?
The quest for new approaches to treat solid tumors is a challenging and complex one. Nonetheless, driven by recent advances in the field and the promise of both scientific and financial rewards, research is ongoing in hopes of significant breakthroughs that will reward the next generation of cancer patients.
Punit Dhillon is president and CEO of OncoSec Medical.