Key Points
MSCs can become cancer-associated fibroblasts and transfer mitochondria to rescue B-ALL cells from ROS-inducing chemotherapy. Rescue of B-ALL cells is overcome by microtubule inhibitors, which interrupt the tunneling nanotubes used for mitochondrial transfer.
Oncolytic virotherapeutic agents are likely to become serious contenders in cancer treatment. The vaccine strain of measles virus is an agent with an impressive range of oncolytic activity in pre-clinical trials with increasing evidence of safety and efficacy in early clinical trials. This paramyxovirus vaccine has a proven safety record and is amenable to careful genetic modification in the laboratory. Overexpression of the measles virus (MV) receptor CD46 in many tumour cells may direct the virus to preferentially enter transformed cells and there is increasing awareness of the importance of nectin-4 and signaling lymphocytic activation molecule (SLAM) in oncolysis. Successful attempts to retarget MV by inserting genes for tumour-specific ligands to antigens such as carcinoembryonic antigen (CEA), CD20, CD38, and by engineering the virus to express synthetic microRNA targeting sequences, and “blinding” the virus to the natural viral receptors are exciting measures to increase viral specificity and enhance the oncolytic effect. Sodium iodine symporter (NIS) can also be expressed by MV, which enables in vivo tracking of MV infection. Radiovirotherapy using MV-NIS, chemo-virotherapy to convert prodrugs to their toxic metabolites, and immune-virotherapy including incorporating antibodies against immune checkpoint inhibitors can also increase the oncolytic potential. Anti-viral host immune responses are a recognized barrier to the success of MV, and approaches such as transporting MV to the tumour sites by carrier cells, are showing promise. MV Clinical trials are producing encouraging preliminary results in ovarian cancer, myeloma and cutaneous non-Hodgkin lymphoma, and the outcome of currently open trials in glioblastoma multiforme, mesothelioma and squamous cell carcinoma are eagerly anticipated.
Glioblastoma multiforme (GBM) is the most common and aggressive malignant brain tumor of the central nervous system and has a very poor prognosis. The current standard of care for patients with GBM involves surgical resection, radiotherapy, and chemotherapy. Unfortunately, conventional therapies have not resulted in significant improvements in the survival outcomes of patients with GBM; therefore, the overall mortality rate remains high. Immunotherapy is a type of cancer treatment that helps the immune system to fight cancer and has shown success in different types of aggressive cancers. Recently, healthcare providers have been actively investigating various immunotherapeutic approaches to treat GBM. We reviewed the most promising immunotherapy candidates for glioblastoma that have achieved encouraging results in clinical trials, focusing on immune checkpoint inhibitors, oncolytic viruses, nonreplicating viral vectors, and chimeric antigen receptor (CAR) immunotherapies.
We showed previously that expressing tumor-associated antigens (TAA) from Vesicular Stomatitis Virus (VSV) eradicates established tumors. We show here that truncation of TAA expressed from VSV can occur to preserve the ability of the virus to replicate efficiently. We observed that truncation of VSV-expressed TAA affects the processing of the antigen, causing a bias towards an IL-17 anti-tumor response which was raised by cumulative signaling from different types of APC, each presenting specific, truncated antigens. Whereas processing of full length, self-TAA invoked an IFN-γ based, CD8+ dependent response, truncated versions of the same self-TAA (likely to be poorly and incompletely folded) were processed through a class II-dependent pathway, and invoked an IL-17 based response. Significantly, the IL-17-mediated anti tumor response was both more therapeutic, and durable, than the response against full length self-TAA. These data show that the type/potency of anti-tumor immune responses against self-TAA can be manipulated in vivo through the nature of the self protein (full length or truncated), inclusion of multiple TAA to recruit the optimal combination of APC, and the resultant skewing of the T cell response to either an IFN-γ or IL-17 producing phenotype. Therefore, in addition to generation of neoantigens through sequence mutation, immunological tolerance against self-TAA can be broken through manipulation of protein integrity, allowing for rational design of better self immunogens for cancer immunotherapy.
S262oncolytic virus. Our results show that Bevacizumab enhances viral distribution as well as tumor hypoxia and enlarges the population of apoptotic cells, and therefore induces a synergistic antitumor effect. It can be a promising virus-associated agent in the anticancer treatment.
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