Lymphoma can be divided into two categories: Hodgkin's lymphoma, and Non-Hodgkin's lymphoma. Hodgkin's disease is a specific kind of lymphoma commonly diagnosed by the appearance of Reed-Sternberg cells in tissue biopsies. Fortunately, Hodgkin's lymphoma is one of the most curable forms of cancer, and patients with this disease have a 5-year survival rate of 85%. However, Non-Hodgkin's lymphoma is the more common type of lymphoma, and covers a range of lymphatic cancers, including: diffuse large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, marginal zone B-cell lymphoma, burkitt lymphoma, lymphoplasmacytic lymphoma, hairy cell leukemia, primary central nervous system lymphoma, precursor T-lymphoblastic lymphoma and peripheral T-cell lymphomas.
The most common form of non-Hodgkin's lymphoma is diffuse large B-cell lymphoma. Patients with this disease have poor survival with a 5 year survival rate as low as 58%. The treatment success rates and prognosis heavily depend on the stage at which the disease is diagnosed. Both, Hodgkin's and non-Hodgkin's lymphoma are staged according to the Ann Arbor staging system, which stages a cancer from I to IV. The number represents the extent to which the cancer has spread, with stages I-III representing one to three cancerous lymph nodes, respectively. Stage IV marks disseminated disease that has spread into secondary organs away from the main sites of disease. Depending on the disease staging at the time of diagnoses, the treatment regime differs: For example, for patients with non-Hodgkin's lymphoma stage I/II, the clinical protocol calls for a combination therapy of Rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (R-CHOP) for 3-4 cycles. In the advanced stages III and IV, R-CHOP is administered for 6 cycles, sometimes with involved-field radiation therapy (IFRT). In cases of relapse, the patient may be administered platinum based chemotherapy, radio-immunotherapy, and higher doses of previous chemotherapeutics. Chen et al., Expert Opin. Drug Deliv., vol. 2, no. 5, pp. 873-890 (2005).
It is clear that novel and innovative therapeutic strategies are needed to increase the survival rates as well as to mitigate the adverse side effects associated with many of the treatment regimes described above. Key strategies include to device methods to lower the effective dose of systemically administered toxic drugs—this can be achieved through targeted drug delivery strategies thereby increasing the partitioning of the drug to the site of the disease.
One avenue of disease-specific drug targeting is found in the application of antibodies, and more specifically antibody-drug conjugates (ADCs). Bouchard et al., Bioorg. Med. Chem. Lett., vol. 24, no. 23, pp. 5357-5363 (2014). Antibodies can be selected to virtually any disease target; the antibody itself can be therapeutic or can carry a therapeutic cargo. Drug-targeting my means of antibody target-antigen specificity holds great potential for cancer therapy. Tumor neoantigens have been discovered allowing the selection of target-specific antibodies, therefore allowing drug targeting. Immunotherapies are gaining momentum not only in clinical trials, but such biological therapies have become a clinical reality. A notable example is the monoclonal antibodies therapy rituximab. Rituximab targets CD20, which is a protein expressed on most non-Hodgkin's B-cell lymphoma. The CD20 target is not normally found in circulation, therefore making this therapy highly specific. Rituximab is the standard for patients diagnosed with non-Hodgkin's B-cell lymphoma, yet the survival rates are only 58%, indicating there is still room for improvement. Feugier et al., J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol., vol. 23, no. 18, pp. 4117-4126 (2005).
Another avenue toward targeted therapies is the development of nanoparticles. Nanoparticles typically measure between 10-500 nm and are thus small enough to efficiently navigate circulation, traffic through tissues and target and enter cells. Albanese et al., Annu. Rev. Biomed. Eng., vol. 14, no. 1, pp. 1-16 (2012); Yildiz et al., Curr. Opin. Biotechnol., vol. 22, no. 6, pp. 901-908 (2011). Nanoparticles are larger than antibodies and offer multivalency; i.e., while an IgG antibody offers two binding sites for antigen binding, a nanoparticle has the potential to bind to multiple hundred-to-thousands of binding sites. The multivalency provides a mechanism to increase target specificity through added avidity effects. Furthermore, multifunctional designs are possible, where toxic payloads and/or contrast agents are loaded into the nanoparticle while targeting ligands enable tissue-specific delivery with increased payload delivery. M. Wu and Z. Niu, Nanoparticles for Biotherapeutic Delivery (Volume 1), Future Science Ltd, pp. 50-62 (2015); Xiao et al., Cancer Res., vol. 72, no. 8, pp. 2100-2110, (2012).
Nanoparticles take advantage of their size and shape to gain increased uptake into tumor vasculature. Rapid angiogenesis occurs to supply the tumor with nutrients and oxygen and support the increased growth—as a result the neovasculature is leaky with a porous endothelium. This leaky vasculature with pores at the nano-to-micron size, create the perfect entry ways for nanoparticles to enter the tumor. Wong et al., PLoS ONE, vol. 10, no. 5, (2015) Simultaneously, the microenvironment created by the angiogenesis causes local compressive forces, which in turn lead to poor lymphatic drainage. This effect is known as the enhanced permeability and retention effect (EPR). Simply by flowing through the bloodstream, the nanoparticles are likely to extravasate into the tumor, and stay in that environment due to the EPR effect. Some nanoparticles, such as doxil, a liposomal formulation of doxorubicin, have been clinically approved for treatments in ovarian cancer, AIDS-related Kaposi sarcoma, and multiple myeloma. Nevertheless, while the research development pipeline is moving rapidly, nanoparticle therapies have not yet made it into the standard of care for non-Hodgkin's-lymphoma. Rink et al., Curr. Opin. Oncol., vol. 25, no. 6, pp. 646-651 (2013). Of course, the EPR effect does not hold count for blood cancers such as non-Hodgkin's-lymphoma. Alternative methods must be developed to target potent therapies to this disease.