Wilgenhof S.,UZ Brussel |
Wilgenhof S.,Laboratory of Molecular and Cellular Therapy |
Van Nuffel A.M.T.,Laboratory of Molecular and Cellular Therapy |
Corthals J.,Laboratory of Molecular and Cellular Therapy |
And 9 more authors.
Journal of Immunotherapy | Year: 2011
The immunostimulatory capacity of dendritic cells is improved by co-electroporation with mRNA encoding CD40 ligand, constitutively active toll-like receptor 4, and CD70 (TriMix-DC). This pilot clinical trial evaluated the feasibility, safety, and immunogenicity of a therapeutic vaccination containing autologous TriMix-DC co-electroporated with mRNA encoding a human leukocyte antigen class II-targeting signal linked to 1 of 4 melanoma-associated antigens (MAGE-A3, MAGE-C2, tyrosinase, and gp100) in patients with advanced melanoma. Thirty-five American Joint Committee on Cancer stage III/IV melanoma patients received autologous TriMix-DC (4 administrations 2 weeks apart). Immune monitoring was performed by evaluating skin biopsies of delayed type IV hypersensitivity (DTH) reactions for presence of vaccinal antigen-specific DTH-infiltrating lymphocytes (DIL). Thereafter, patients could receive interferon-alpha-2b (IFN-α-2b) 5 MU subcutaneously 3 times weekly and additional TriMix-DC every 8 weeks. TriMix-DC-related adverse events comprised grade 2 local injection site reactions (all patients), and grade 2 fever and lethargy (2 patients). Vaccinal antigen-specific DIL were found in 0/6 patients tested at vaccine initiation and in 12/21 (57.1%) assessed after the fourth vaccine. A positive postvaccination DTH test correlated with IL-12p70 secretion capacity of TriMix-DC. No objective responses to TriMix-DC alone were seen according to RECIST. Twenty-nine patients received IFN-α-2b after the fourth vaccine without unexpected adverse events. During TriMix-DC/IFN-α- 2b combination therapy, 1 partial response and 5 stable disease (disease control of >6 months with regression of metastases) were observed in 17 patients with evaluable disease at baseline. In conclusion, this study demonstrated that therapeutic vaccination with autologous TriMix-DC is feasible, safe, and immunogenic and can be combined with sequential IFN-α-2b. Copyright © 2011 by Lippincott Williams &Wilkins.
Researchers in Argentina say they have genetically modified an adenovirus - which can cause colds, conjunctivitis and bronchitis - to home in on cancer, killing tumor cells in patients without harming healthy tissue. Scientists have long been intrigued by the idea of using viruses to alert the immune system to seek and destroy cancerous cells. That interest has taken off in recent years as advances in genetic engineering allow them to customize viruses that target tumors. Dr. Osvaldo Podhjacer, Chief of the Laboratory of Molecular and Cellular Therapy at the Fundacion Instituto Leloir in Buenos Aires, and his team developed an 'oncolytic' virus designed to target both malignant cells and tumor-associated stromal cells. In February, Unleash Immuno Oncolytics announced it had entered a license agreement with Leloir Institute to develop immuno-oncology products for cancer treatment in Saint Louis. Unleash's leading product, developed thanks to work by Podhjacer, is called UIO-512. Dr. Podhjacer explained how the virus helps to attack cancer. "This is a virus, which, by genetic modification, we have restricted their infectivity exclusively to malignant cells, in spite of the fact, originally, the virus can infect normal cells and cause colds, conjunctivitis and bronchitis. Why immunotherapy? Because in addition to the changes we have made to restrict the infection only to malignant cells, it also has a gene that exacerbates the immune response. Then there is a direct attack on the tumor initial and an additional immunological response which in principle eliminates the residual tumor, which was not eliminated by the virus and disseminated metastases," Dr. Podhjacer said. Scientific journal Nature reported in October last year that cancer-fighting viruses had started to win approval. Researchers hope that ongoing clinical trials of similar oncolytic viruses and their approval will generate the enthusiasm and cash needed to spur further development of the approach. "These viruses are very effective in pre-clinical models of cancer, we have tested and in particular, ovarian cancer and melanoma but we also have other viruses for pancreatic and colon rectal cancer. These are non-toxic and they are as important as their therapeutic efficacy, where we have managed to reverse the levels of liver enzymes to a normal level with animals that have a tumor. These levels become very high due to the toxicity. In general terms, it allows us to qualify this virus as an ideal candidate to be taken to a clinical trial in humans beings," Dr. Podhjacer, said. Professor Lawrence Young, a cancer specialist from the University of Warwick, said that while similar research has been ongoing for many years, Podhjacer's team had added a mechanism to influence the cells surrounding the cancer tumor. "To be honest, it's not particularly novel. What they have done, however, which is a bit interesting is introduce a new bell or a new whistle, if you like, in terms of the virus, which is to also have an effect on some of the supporting cells. So one of the things that's very exciting about current cancer biology is an increased understanding of the fact that while you've got cancer cells and tumor cells, which are important targets; actually there's a lot of supporting cells around the cancer that also get modified in that environment and start to mis-behave," Young told Reuters. Podhajcer said that the virus attacks the entire tumor mass, not only the malignant cells themselves but also the stromal cells that support cancer dissemination. "We have prepared a virus with the ability to study everything that is characteristic of the tumor and to attack all the cells of the tumor. In other words, we have an approach different to what has been done to this day today, even within what is being used in the oncolytic therapy using these viruses which also generate secondary immune responses. In other words, it is a disruptive technology and we also add something that is unique to our research," Podhajcer said. Professor Young cautioned that there are a number of hurdles for the therapy to overcome. In addition to the cost implications for eventually making it widely available, he said that the body's own immune system could make subsequent doses of a treatment increasingly less effective. "Some of those immune responses will target the tumor, some won't. And so the degree to which you can re-use these viruses is a problem because as you get an immune response to them, as soon as you then expose a patient to a second or third dose their immune system starts to think "wait a minute, we've seen that before, we're going to wipe it out". So these are very challenging therapies," he said. According to the journal Nature, the strategy builds on a phenomenon which has been recognized for more than a century. Physicians in the 1800s first noted their cancer patients sometimes unexpectedly went into remission after experiencing a viral infection. Based on these reports, doctors in the 1950s and 1960s were then inspired to start injecting cancer patients with a menagerie of viruses. Sometimes the therapy destroyed the tumor, and on occasion it killed the person instead. According to Professor Young, however, the field of immunotherapy has advanced rapidly in the past ten years and there is a great deal of positivity for what the future holds in the fight against cancer. "I think that there's so much excitement about this now, and so much excitement about being able to use non-viral approaches to delivering drugs and genes, that it's quite clear that over the next ten years or so, we're going to see more of these therapies, especially in the more difficult to manage tumors," he said.