The role of cell-mediated cytolysis in antitumor responses

The purpose of the work described in this thesis was (1) to study the effector cell types involved in antitumor responses; (2) to investigate whether of the immune system in cancer patient may occur at tumor-target or at lymphocyte-effector cell level; and (3) to explore new strategies for producing tools for immunotherapy of cancer, i.e. enhancement of cytotoxic activity to optimal levels by BRM, and production of immortalized cytotoxic lymphocytes with stable lytic functions. The major conclusions that can be drawn from the results obtained are the following: 1. From the three lymphoid (sub) populations studied i.e. TCR-/CD3- NK, TCRa~+/CD3+ and TCRyo+/CD3+ CTL clones, TCRyo+/CD3+, TCRa~+/CD3+ CTL appeared to have the widest target cell spectrum and to exert the highest level of CTX against fresh tumor cells. 2. The failure of the immune system in the cancer patients we studied seems located at the level of the CDS+ lymphocyte, possibly tumor cell induced. This may be due to a defective signal transduction mechanism. 3. Cytolytic activity of TCR-/CD3- NK and TCRa~+/CD3+ T-cell clones against tumor cells can be successfully enhanced, i.e. lymphocyte clones that were already active could be stimulated further by OK-432 and IL-2. 4. In an attempt to immortalize cytotoxic lymphocytes by somatic cell hybridization, an efficient electrofusion system was developed for the first time, allowing to produce T- and NK-cell hybridomas routinely. In spite of the large number of hybridomas generated, only a few were transiently cytolytic. This is most likely due to chromosomal instability of the hybridomas. As suggested by our studies and those of others, DNA-mediated transfer of multiple genes, for instance e-ras, c-myc, PS3 and the IL-2R gene, involved in cell differentiation and proliferation may be an alternative strategy to immortalize cytotoxic lymphocytes

Reverse geroscience: how does exposure to early diseases accelerate the age‐related decline in health?

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135360/1/nyas13297.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135360/2/nyas13297_am.pd

Antitumoral effects of attenuated Listeria monocytogenes in a genetically engineered mouse model of melanoma

Attenuated Listeria monocytogenes (Lmat-LLO) represents a valuable anticancer vaccine and drug delivery platform. Here we show that in vitro Lmat-LLO causes ROS production and, in turn, apoptotic killing of a wide variety of melanoma cells, irrespectively of their stage, mutational status, sensitivity to BRAF inhibitors or degree of stemness. We also show that, when administered in the therapeutic setting to Braf/Pten genetically engineered mice, Lmat-LLO causes a strong decrease in the size and volume of primary melanoma tumors, as well as a reduction of the metastatic burden. At the molecular level, we confirm that the anti-melanoma activity exerted in vivo by Lmat-LLO depends also on its ability to potentiate the immune response of the organism against the infected tumor. Our data pave the way to the preclinical testing of listeria-based immunotherapeutic strategies against metastatic melanoma, using a genetically engineered mouse rather than xenograft models

White paper on microbial anti-cancer therapy and prevention

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting (‘Microbial Based Cancer Therapy’) at the US National Cancer Institute in the summer of 2017. Here, we define ‘Microbial Therapy’ to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care