Treatment of cancer using recall antigens delivered by attenuated bacteria
Methods, pharmaceutical compositions and vaccines comprising an attenuated bacteria that expresses a recall antigen are disclosed for treatment of cancer.
1. An arrangement, in a tumor microenvironment in a subject, of a cancer immunotherapy compound and a chemotherapeutic compound,
the cancer immunotherapy compound having exited a first myeloid-derived suppressor cell in the tumor microenvironment and entering a tumor cell in the tumor microenvironment,
the chemotherapeutic compound causing cell death in a second myeloid-derived suppressor cell in the tumor microenvironment,
the cancer immunotherapy compound comprising:
an attenuated bacteria configured to induce an immune response in the subject to the tumor cell substantially at least equal in magnitude to an immune response in the subject to a pathogen recognized by the immune system of the subject, the attenuated bacteria configuration including having as a payload a fusion of a truncated non-cytolytic Listeriolysin-O and a non-self external antigen of the pathogen, the payload lacking a cancer specific antigen, the Listeriolysin-O including a signal sequence for inducing the tumor cell to present the non-self external antigen on an external surface of the tumor cell, wherein
an intraperitoneal injection of the cancer immunotherapy compound into the subject permits survival of the cancer immunotherapy compound until the attenuated bacteria infects the first myeloid-derived suppressor cell,
travel of the first myeloid-derived suppressor cell to the tumor microenvironment, and subsequent exit, facilitated by the Listeriolysin-O, of the cancer immunotherapy compound from the first myeloid-derived suppressor cell, delivers the cancer immunotherapy compound to the tumor microenvironment,
infection of the tumor cell by the cancer immunotherapy compound, facilitated by immune suppression in the tumor microenvironment caused at least in part by the second myeloid-derived suppressor cell prior to the cell death, and subsequent secretion by the cancer immunotherapy compound of the payload in the tumor cell causes the tumor cell, in response to the signal sequence, to present the non-self external antigen on the external surface of the tumor cell,
recognition of the non-self external antigen by the immune system causes the immune response to the tumor cell, and
the immune response is enhanced by a reduction of immune suppression in the tumor microenvironment caused by the cell death caused by the chemotherapeutic compound.
2. The arrangement of claim 1 , wherein the attenuated bacteria is an attenuated strain of one or more of Listeria monocytogenes, Salmonella thyphimurium, Vibrio cholera, Clostridium , and Bifidobacterium breve.
3. The arrangement of claim 1 , wherein the non-self external antigen is an epitope of one or more of tetanus toxoid, measle virus, and polio virus.
4. The arrangement of claim 1 , wherein the chemotherapeutic compound is gemcitabine.
5. The arrangement of claim 1 , wherein the subject is a target subject and the arrangement includes, with regard to 10 4 CFU of the cancer immunotherapy compound and 1.2 mg of the chemotherapeutic compound being clinically effective for a mouse subject, the corresponding clinically effective respective amounts of the cancer immunotherapy compound and the chemotherapeutic compound for the target subject.