Cancer immunotherapy research has exploded in recent years. Since the approval of the first antibody treatment for cancer in 1997, the number of publications in the space has increased exponentially year over year.1 Combination therapies - immunotherapy agents with other drugs or modalities - have become a popular area of research and development.
Immunotherapy harnesses the power of the immune system to attack and eliminate cancer cells. The immune system is able to recognize and eliminate tumor cells, but due to interference of the tumor in the immune response, it often benefits from a boost to the natural pathway.
The earliest cancer vaccines relied on monoclonal antibodies to target cancer cells for elimination by the immune system. Increasingly, researchers are linking antibodies to more powerful cancer-killing technologies to increase the effect of the treatments.
Examples include CAR T-cell therapy, antibody-drug conjugates, radiolabelled antibodies, and bispecific monoclonal antibodies.
Magnetic nanoparticles have been successfully combined with immunotherapy approaches to target hyperthermia treatments to cancer cells. This strategy is an attractive area for new investigations.
A new, off-the-shelf magnetic hyperthermia system from nanoTherics Ltc. enables cancer immunotherapy using magnetic nanoparticles in vitro and in vivo. With the use of the magneTherm system, heating effects of immunotherapeutic nanoparticles can be readily evaluated and developed for the clinic.
Hyperthermia - an Effective Cancer Killing Strategy?
Hyperthermia is another promising treatment approach that can work synergistically with immunotherapy for cancer treatment. In hyperthermia therapy, the temperature of the body or a disease location is heated above normal temperatures.
There are several mechanisms by which hyperthermia can eliminate cancer cells. One is that heat increases the visibility of the tumor cells to the immune system by increasing surface expression of certain antigens, allowing increased recognition by CD8+ T cells.
Another way that heat can affect tumor cells, depending on the temperature range and duration of heating, is by heat shock, where cells express specific proteins which increase the sensitivity of the immune system to the cells.2, 3
The typical method for therapeutic hyperthermia in cancer treatment has been capacitive heating using a radiofrequency (RF) electric field. In RF heating, a high frequency alternating electric field heats a material through rotation of molecular dipoles within the material. Different heating ranges can be used.
A range of 39 to 41 ℃ mimics a natural fever, and can be used throughout the body. More effective heating, at temperatures of 41 to 45 ℃, are typically used to induce cell death, and some applications use temperatures as high as 80 ℃ for tumor ablation.4, 5, 6
The use of this method has been limited, however, because it is difficult to precisely heat the tumor without damaging normal tissue.
Magnetic Nanoparticles as a Tool for Therapeutic Hyperthermia
Magnetic nanoparticles can overcome some of the limitations of traditional RF hyperthermia, and have been tested in some therapeutic applications. Because they can be manipulated using a magnetic field, they also have utility for drug targeting and bioseparations.
Magnetite cationic liposomes (MCL) act as carriers to introduce magnetite nanoparticles into target cells.7 The positively charged surface of the MCL interacts with the negatively charged cell surface.
When conjugated with antibodies, to create antibody-conjugated magnetoliposomes, the MCL can be targeted to a specific tumor. The combined approach has potential for a significant added immune response over and above existing therapies.
In a study of subcutaneous mouse melanoma, investigators successfully used MCLs to heat tumor cells while minimizing heating of healthy tissue.9 Tumor temperatures rose quickly to the target temperature of 43 ℃, while the rectal temperature of the mouse remained at 37 ℃.
Although the 43 ℃ temperature was insufficient to destroy the tumor, the study showed that the intracellular hyperthermia using MCLs was able to heat the tumor with accurate control through magnetic field intensity.
In other studies, the same researchers observed 90 percent regression of B16 melanoma in mice using the hyperthermia system at 46 ℃, once daily, for two days.8
Because the system killed tumor cells through expression of HSP70-tumor antigen complexes at the tumor site, and recruited immune effector cells, intracellular hyperthermia using MCLs may be considered as an in situ vaccination therapy for cancer.
In a subsequent study, researchers investigated the effects of MCL-induced hyperthermia combined with dendritic cell therapy on mouse melanoma. Dendritic cells are potent antigen-presenting cells that are able to take up and mature antigen to induce an immune response.
Dendritic cells act as cellular sensors of microbes. They capture invading microbes and pass the information to the lymphocytes, providing a link between the innate and adaptive immune responses. Similarly, dendritic cells present tumor antigens to the immune system to create anti-tumor immunity.
However, tumor cells themselves are very poor antigen-presenting cells. The strategy of vaccination with dendritic cells, then, is to provide the dendritic cells with tumor-specific antigens.10
Some typical methods for loading dendritic cells with antigens are pulsing with tumor proteins or peptides, transfecting them with tumor antigen genes, and fusing dendritic cells with tumor cells.
The investigators chose to inject the immature dendritic cells into the tumor in situ. Since HSP70 has been shown to enhance antigen uptake by dendritic cells and to induce dendritic cell maturation, using MCLs to heat the cells to the appropriate temperature to release HSP70 would be expected to trigger maturation of the dendritic cells and uptake of the tumor antigens, resulting in an immune response to the tumor.
Mice were divided into four groups, a control group, a hyperthermia-only group, a dendritic cells-only group, and a combination hyperthermia and dendritic cells group.
Sixty percent of mice in the combination group had complete regression of tumors, while none of the mice in the other groups showed any regression.
The results support further study of dendritic cell immunotherapy combined with hyperthermia in humans as a novel cancer treatment.
Magnetic hyperthermia combined with immunotherapy has significant potential for clinical application. In order to optimize that potential, researchers will need to fine tune many variables such as heating temperature, heating time, treatment timing, and therapeutic readout. More exploration of the interactions of hyperthermia with other therapies will be needed, as well.
If immune activation depends on release of heat shock proteins like HSP70, there may be effects on other therapies that also depend on HSPs for their efficacy, creating potential for both synergy and interference, depending on the mechanisms.
Further study of the biology of cell death by hyperthermia will support further development of therapeutic applications.
Enabling synergistic immune and hyperthermia therapies
Nanotherics has developed a unique, competitively priced system enabling synergistic immune and hyperthermia therapies. It operates at a wide range of frequencies in a single system with no extra components required.
The magneTherm system is ideally suited for cancer studies with real time cellular capability and in vivo options.
- Razvi, E., & Oosta, G. (2016, May 2). Cancer Immunotherapy 2016. Genetic Engineering and Biotechnology News.
- den Brok MH, Sutmuller RP, van der Voort R, Bennink EJ, Figdor CG, Ruers TJ, et al. In situ tumor ablation creates an antigen source for the generation of antitumor immunity. Cancer Res 2004; 64:4024–9.
- Palucka, K., & Banchereau, J. (2013). Cancer Immunotherapy via Dendritic Cells. Interaction of Immune and Cancer Cells, 75-89. doi:10.1007/978-3-7091-1300-4_4
- Toraya-Brown, S., & Fiering, S. (2014). Local tumor hyperthermia as immunotherapy for metastatic cancer. International Journal of Hyperthermia, 30(8), 531-539. doi:10.3109/02656736.2014.968640
- Zee, J. V. (2002). Heating the patient: A promising approach? Annals of Oncology, 13(8), 1173-1184. doi:10.1093/annonc/mdf280
- Wust, P., Hildebrandt, B., Sreenivasa, G., Rau, B., Gellerman, J., Reiss, H., Schlag, P. M. (2002, August). Hyperthermia in combined treatment of cancer. Lancet Oncol, 3(8), 487-497.
- Ito, A., Shinkai, M., Honda, H., & Kobayashi, T. (2005). Medical application of functionalized magnetic nanoparticles. Journal of Bioscience and Bioengineering, 100(1), 1-11. doi:10.1263/jbb.100.1
- Ito, A., Tanaka, K., Kondo, K., Shinkai, M., Honda, H., Matsumoto, K., . . . Kobayashi, T. (2003). Tumor regression by combined immunotherapy and hyperthermia using magnetic nanoparticles in an experimental subcutaneous murine melanoma. Cancer Science, 94(3), 308-313. doi:10.1111/j.1349-7006.2003.tb01438.x
- Suzuki, M., Shinkai, M., Honda, H., & Kobayashi, T. (2003). Anticancer effect and immune induction by hyperthermia of malignant melanoma using magnetite cationic liposomes. Melanoma Research, 13(2), 129-135. doi:10.1097/00008390-200304000-00004
- Ito, A., Honda, H., & Kobayashi, T. (2005). Cancer immunotherapy based on intracellular hyperthermia using magnetite nanoparticles: A novel concept of “heat-controlled necrosis” with heat shock protein expression. Cancer Immunology, Immunotherapy Cancer Immunol Immunother, 55(3), 320-328. doi:10.1007/s00262-005-0049-y
nanoTherics are based in Staffordshire, United Kingdom. Their mission is to become the leading supplier of IP protected products addressing the field of magnetic nanoparticle research and applications. In particular they aim to be the number one supplier of products for nanoparticle heating applications utilizing AC field and solenoid coil principles.
They also apply their significant know how in magnetic nanoparticles to the field of transfection devices and reagents for biomaterial delivery into cells for the life science research and development market and reagents for biomaterial delivery into cells for the life science research and development market.
Their aim is to provide superior performance magnetic based tools to address global markets and to underpin the research and development of current and future nanoparticle, magnetic particle, cancer therapy, drug delivery, genetic screening and gene therapy programs.
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