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Cancer Immunotherapy Set for Human Trials
Few statements in medical science are met with as much skepticism as the words, “We found a cure for cancer.” Cancer is a description given to more than 100 distinct diseases, affecting almost every part of the body. Cancer is caused when normal cells accumulate various mutations, or changes to the DNA that remove normal barriers to cellular replication. Thus, the mutated cancerous cell can replicate more frequently than normal cells, causing a tumor. If enough mutations accumulate, the cancerous cells can begin to leave the original site, and spread, or metastasize, to other parts of the body. Different types of cancers result from different combinations of mutations to factors that regulate cell growth and replication. To find one cure for all cancers seems like an impossible goal, given the various causes, locations, and types of cancers.

One great hope for cancer treatments comes from the host immune system. Normally, when either a foreign cell or a defective host cell is present in the body, the immune system will attempt to kill the cell. This prevents disease, such as infection or cancer. However, many cancer cells are able to evade the host’s immune system, by producing and displaying proteins that tell the host they are normal.

One such protein that is found on normal human cells is CD47. In normal cells, CD47 is expressed at a low level that is still sufficient to protect them from the immune system. Cancer cells, on the other hand, express very high levels of CD47. In 2012, researchers found that anti-CD47 antibody was able to target human-origin tumor cells in mice. The antibody, which binds to CD47 and makes it ‘invisible’ to immune cells, allowed macrophages and other phagocytes to destroy the tumor cells. This prevented tumor growth, and in some cases even decreased the size of the tumors. Shrinking tumors and preventing growth can help prevent the spread of cancer to other parts of the body.

The anti-CD47 antibody was effective at reducing the size and growth of a variety of human tumors, including breast cancer, bladder cancer, glioblastoma, lung cancer, and ovarian cancer. In many mice, the tumor was completely destroyed, and the mice remained cancer free several months after the study was completed. Additionally, the antibody did not show severe toxic reactions in the mice; only short-term anemia was noted. This is because cancer cells have a much higher number of CD47 molecules on their surface than normal cells, so they are targeted much more efficiently by the CD47 antibody. This lack of toxicity is a drastic change from conventional cancer therapies, such as chemotherapy and radiation, which work by targeting and killing all rapidly-multiplying cells.

Now, clinical trials are being prepared to test the efficacy of anti-CD47 antibody in human patients, and hopefully will begin in 2014. It is a difficult process to move from animal-based studies into clinical trials for many reasons. The antibody used in the clinical trials must be ‘humanized’ so that it interacts with the correct cells. In addition, the antibody must be produced in large quantities under very exacting conditions to ensure safety. The setup of the clinical trial must also be carefully planned, so that any data obtained can be properly interpreted. Investigators must determine how much antibody to give, which patients will be eligible, how to compare study results to placebo results, and more.

While this news is exciting, given the variety of cancers the anti-CD47 antibody was able to recognize, it must be met with cautious optimism. The natural tumors found in human patients may have key differences from the transplanted tumors in the mice. For example, these tumor cells may have other defense mechanisms in place to protect against the immune system. In addition, not all tumors may be good targets for the anti-CD47 immunotherapy. Solid tumors might be the best candidates for this immunotherapy, as the antibody could easily be injected directly into the tumor. However, if the tumor is too large, the antibody might not be able to reach and bind to all the cancer cells, necessitating multiple treatments. Blood cancers, such as lymphoma and leukemia, may not be suitable targets for the antibody. Because they do not consist of solid tumors, it might be difficult to localize the antibody to the cancerous cells. Also, since normal blood cells also express small amounts of CD47, intravenous injection of anti-CD47 antibody might cause more pronounced and long-lasting anemia that what was demonstrated in the mouse models. Despite these concerns, the promises of anti-CD47 immunotherapy could revolutionize future cancer treatments.

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Antibodies and solid tumours

The previous article reports on some promising results obtained in animal studies with an antibody against CD47. The likely main efficacy of this antibody, should it pass the rigours of clinical trial testing, would seem to be for solid tumours. Various monoclonal antibodies have obtained regulatory approval to date as solid tumour therapeutic agents, all with different modes of action. These include trastuzumab, cetuximab, panitumumab, bevacizumab, catumaxomab, ipilimumab and denosumab. They target many different solid tumour types including, for example, breast, colorectal, head and neck, non-small cell lung cancers and melanomas.

As the previous article mentions, one of the challenges in developing a new cancer treatment is in targeting the drug to the tumour cells and in the case of a solid tumour, ensuring all the cancer cells are accessed. Thus much effort has been focused on development of effective drug delivery systems, which may be relevant as anti- CD47 enters clinical trials. One approach that has shown promise is the use of immunoliposomes. Studies are on-going to attempt modifications of liposomes that would allow efficient targeting of incorporated antibodies to their antigens. Nanoparticulate drug carriers are another potential method.

Another approach, which is different to the proposed use of anti-CD47 directly as a therapeutic agent, is to use the antibody to target the tumour and conjugate it to anti-tumour agents so that they can do their work. This has been examined, for example, in targeting alpha (v) integrins with antibody-maytansinoid conjugates containing anti-tumour maytansinoid-linker structures. Coupling of anti-GD2 antibody to liposomes has also been considered as a way to deliver siRNA in a targeted manner to neuroblastoma cells.

It is to be hoped that the promise of CD47 from animal studies will translate into successful clinical trials and drug development.


ADRIAN, J.E. et al., 2011. Targeted delivery to neuroblastoma of novel siRNA-anti-GD2-liposomes prepared by dual asymmetric centrifugation and sterol-based post-insertion method. Pharmaceutical research, 28(9), pp. 2261-2272

CHEN, Q. et al., 2007. Alphav integrin-targeted immunoconjugates regress established human tumors in xenograft models. Clinical Cancer Research: An Official Journal Of The American Association For Cancer Research, 13(12), pp. 3689-3695

DIENSTMANN, R., MARKMAN, B. and TABERNERO, J., 2012. Application of monoclonal antibodies as cancer therapy in solid tumors. Current Clinical Pharmacology, 7(2), pp. 137-145

HOLBACK, H. and YEO, Y., 2011. Intratumoral drug delivery with nanoparticulate carriers. Pharmaceutical research, 28(8), pp. 1819-1830

LEHTINEN, J. et al., 2012. Pre-targeting and direct immunotargeting of liposomal drug carriers to ovarian carcinoma. Plos One, 7(7), pp. e41410-e41410

PASTORINO, F. et al., 2013. Nanocarrier-mediated targeting of tumor and tumor vascular cells improves uptake and penetration of drugs into neuroblastoma. Frontiers In Oncology, 3, pp. 190-190

WILLINGHAM, S.B. et al., 2012. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proceedings of the National Academy of Sciences of the United States of America, 109(17), pp. 6662-6667
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Immunotherapy is a most advanced cancer therapy

Radiation, chemotherapy, and surgery are the conventional methods in the fight against cancer. Radiation was discovered in the 1800's by Marie Curie. Chemotherapy evolved from mustard gas (World War 1), and surgery dates back to the ancient Egyptians.

These treatment modalities are all based on obliterates cancer cells by burning them (irradiation), poisoning them (chemotherapy) or removing them (surgery). While they can effectively kill or remove cancer cells, the use of these treatments often is limited because large numbers of healthy cells also tend to be destroyed. This often results in extreme morbidity and/or disfigurement of the patients treated with them. In the worst cases, these treatments can sometimes result in the patient's death. Starting from the past and till date there is no sure treatment of cancer, and for the reason that of the complexity of cancer biology, it will likely not be within reach. It is now generally settled that the future of cancer therapy lies in the amalgamation of therapies with different mechanisms of action.

As a most modern approach Immunotherapy has come-up for cancer treatment. It is based on the generally-accepted supposition that the immune system is the most excellent tool humans have for fighting disease of bacterial and viral.
Cancer Immunotherapies have the possibility to be used to fighting cancer by either be relevant to external stimulus to the immune system to make it act more vigorously or 'smarter', or by given that the immune system with man-made or naturally-derived tumor specific proteins prepared outside of the body so that the immune system can recognize the tumor as a foreign entity and obliterate it. Immunotherapy is used time to time to care for cancer, but it is most frequently used in amalgamation with customary treatments like radiation, chemotherapy, and surgery in order to improve their effects. One of the potential reimbursements of immunotherapy is that it has the potential not to be as toxic as radiation, chemotherapy, and surgery. In calculation, immunotherapy often may offer a special mode of attack on the tumor, thereby affording both patients and doctors alike a potential new treatment in the fight in opposition to cancer.
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PDS Biotechnology Corporation today presented a summary of the company’s preclinical data on its lead cancer immunotherapy PDS0101 at the World Vaccine Congress in Washington DC. The product is based on the company’s ground-breaking and proprietary Versamune nanotechnology vaccine platform. PDS Biotechnology also announced that the company’s Investigational New Drug (IND) application had been granted by the FDA allowing PDS0101 to be evaluated in human patients.

PDS0101 is a first-in-class immunotherapy being developed to treat cancers and diseases caused by infection with the human papillomavirus such as cervical cancer, head and neck cancer and cervical intraepithelial neoplasia. Dr. Frank Bedu-Addo, President and CEO presented the highly promising preclinical efficacy and safety data demonstrating eradication of the tumors without any of the safety drawbacks typical of the current immunotherapy technologies. PDS0101 is designed to prime the immune system to recruit cells of the body’s own immune system to specifically recognize, target and kill the cancer cells. PDS0101 is also designed to reduce the population of certain immune suppressive cells which prevent our immune systems from detecting and attacking the cancer cells. “Should the preclinical results be replicated in the clinical setting, this will be a giant leap forward in the development of safe and effective cancer therapies”, said Frank Bedu-Addo.

Versamune is a nanotechnology-based immune modulating technology which acts by a novel mechanism to prime and activate the immune system to recognize specific diseased cells and disease causing agents. The technology is unique in its multiple-mode-of-action enabling simple and effective disease-targeting vaccines and immunotherapies to be developed.
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