Melanoma Drug Delivery Approaches Advancing

Image: University of Pennsylvania

Lynn M. Schuchter, MD

Several novel approaches to the delivery of therapeutics for advanced melanoma may improve treatment efficacy and patient survival. These approaches include injecting immunotherapies into the tumor, delivering individual immunotherapies in combination, and using nanoparticle carriers to enhance drug delivery.

Researchers and drug companies are currently investing heavily in immunotherapy treatments for melanoma. These agents are designed to induce or enhance an anticancer response in immune cells that commonly infiltrate melanomas, but don’t usually attack the tumor.

Delivery of the talimogene laherparepvec (T-VEC) vaccine involves injecting the immunotherapy directly into the melanoma. When injected into the tumor, this oncolytic vaccine causes tumor membranes to rupture while triggering an anticancer immune response.

In September, Amgen, the company that produces T-VEC announced the submission of a marketing authorization application for the oncolytic vaccine to the European Medicines Agency as treatment for regional or distant melanoma metastases in adults. This submission “brings us a step closer to helping address an unmet medical need for patients with metastatic melanoma,” stated Sean Harper, MD, Amgen’s chief of research and development.

While the pioneering approach of using therapeutic cancer vaccines has suffered setbacks in the clinical pipeline, delivering T-VEC directly into melanomas in combination with other therapeutic agents, including checkpoint inhibitors, may enhance efficacy.¹

Checkpoint inhibitors are pharmacologic immunotherapies that target immune suppressors such as PD-1 or CTLA-4. Inhibitors of PD-1 (Keytruda), or CTLA-4 (Yervoy), take the “stop signal” away from inactive immune cells, allowing them to attack cancer cells. Targeting “PD-1 is truly a game-changer,” said oncologist Lynn M. Schuchter, MD, in a statement toThe Wall Street Journalin June 2014.

Combining checkpoint inhibitors with oncolytic vaccines has the potential to elicit longer-lasting responses while limiting serious side effects. There are currently more than 19 ongoing clinical trials in melanoma patients pairing immunotherapy treatments with T-Vec, or targeted therapies such as the BRAF inhibitor, vemurafenib.²Importantly, the majority of these trials administer the therapies sequentially to limit toxicity.

In addition to delivering therapeutics in combination to improve efficacy, research is being done on delivering drugs to patients with nanoparticle carriers. In melanoma studies, drug-loaded nanoparticles have reduced toxicity and enhanced efficacy by improving drug specificity, pharmacokinetics, and solubility.³

Nanoparticles tested for melanoma therapy include liposomes, micelles, dendrimers, polymersomes, carbon-based nanoparticles, inorganic nanoparticles and protein-based nanoparticles. Some, such as inorganic gold nanoparticles, have the added benefit of being used as a diagnostic tool during MRI scans.³

While much of the data concerning nanoparticle use for melanoma drug delivery is preclinical, one liposomal formulation, Doxil, is approved for clinical use. Doxil consists of doxorubicin hydrochloride encapsulated in liposomes, and is administered intravenously. However, acquired resistance to Doxil has been an issue in patients with melanoma, and researchers are exploring the efficacy of novel liposomal-based therapies. Gavin Roberts, MD, and colleagues at Penn State College of Medicine have researched a liposomal-based approach to deliver a novel drug, leelamine, to melanoma tumors in mice.⁴The study, reported in the journal of Molecular Cancer Therapy in October 2014, emphasized that leelamine alone could not be taken orally due to poor intestinal uptake or delivered intravenously as it damages red blood cells. With the use of liposomes, “We now have a drug that has the potential to be given to humans that could not be done before,” stated Roberts.

The particle/drug combination named Nanolipolee-007 inhibits multiple effector proteins known to promote melanoma tumor growth, including PI3K, MAPK, and STAT3. Roberts is optimistic that targeting multiple melanoma pathways with one therapy could slow the development of resistance.

The discovery of Nanolipolee-007 has been patented by Penn State and licensed to Melanovus Oncology for upcoming US Food and Drug Administration (FDA)-required research before clinical testing.

There may not be an optimal treatment regimen for every patient with melanoma, but novel and complementary approaches to the delivery of therapeutics are resulting in dramatic improvements in toxicity, efficacy, and survival in patients with advanced melanoma.

Clinical Pearls

1. Puzanov I, Milhem MM, Andtbacka RHI, et al. Primary analysis of a phase 1b multicenter trial to evaluate safety and efficacy of talimogene laherparepvec (T-VEC) and ipilimumab (ipi) in previously untreated, unresected stage IIIB-IV melanoma.J Clin Oncol. 2014;32:5s.
2. Shtivelman E. Immune system-activating drugs in combination treatments may be the next big thing for melanoma. [CancerCommons Website]. Available at: http://www.cancercommons.org/2014/10/20/immune-system-activating-drugs-in-combination-treatments-may-be-next-big-thing-for-melanoma/. Accessed November 15, 2014.
3. Dianzani C, Zara GP, Maina G, et al. Drug delivery nanoparticles in skin cancers.Biomed Res. Int. 2014;2014:895986.
4. Gowda R, Madhunapantula S V, Sharma A, Kuzu OF, Robertson GP. Nanolipolee-007, a novel nanoparticle-based drug containing leelamine for the treatment of melanoma.Mol. Cancer Ther. 2014;13(10):2328-2340.

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