We would like to start a company to bring our powerful Listeria-recall antigen-based therapy against metastatic cancer at old age to the clinic. However, a company has not been started yet. Instead of a business plan, we have included our preliminary results with Listeria-recall antigen-based therapies. There was no match for spontaneous age-related cancer under diseases, and therefore I used breast cancer instead. For the minimum investment I used the direct costs for the proposed project and for the required investment the direct costs plus indirect costs.
While great improvements have been made in the treatment of age-related diseases such as heart disease, type-2 diabetes, and even Alzheimer's Disease, for metastatic cancer there is no cure. Cancer is a disease of the elderly, with metastatic cancer responsible for ∼90% of all cancer mortality. The current gold standard for treatment includes surgery, followed by chemotherapy or radiation, all of which poorly target metastases. Currently, cancer immunotherapy has generated enormous interest because it manipulates the patient’s own T cells to destroy their tumors and metastases. However, major hurdles still need to be overcome, most notably the decline in T cell functions during aging (called immunosenescence), which is the most likely reason for current treatment failures in T cell immunotherapy.
We developed a mode of cancer immunotherapy that takes immunosenescence into account. Using an attenuated bacterium, Listeria monocytogenes (Listeria), we can deliver so-called recall antigens (Listeria-RA) directly into tumor cells with high efficiency. This is possible because this attenuated Listeria selectively infects tumor cells (see below). Recall antigens are antigens to which the cancer patient has been exposed early in life, such as tetanus toxoid (TT), measlevirus (MV) and poliovirus (PV). Virtually all individuals have nowadays been vaccinated against such diseases resulting in memory T cells, circulating in blood for life, that can be reactivated by Listeria-RA at any time, even at old age, and then kill the Listeria-RA-infected tumor cells. So, even if in an aged cancer patient there are no longer well-functioning T cells, the existing memory T cells can still mount a very powerful immune response.
An interesting aspect of our approach is that it turns one of the tumor's strengths (its capacity to suppress the immune response in its immediate surroundings) into a weakness. Indeed, while even the immune response of an aged individual can easily remove our attenuated Listeria variant from healthy tissues (there are virtually no side effects!), it cannot do so in the immediate environment of the tumor cells due to immune suppression. This allows the Listeria to selectively survive and multiply in the tumors and metastases but not in healthy tissues, as mentioned above (Fig 1, Attachment 1). Moreover, as we discovered in the past, Listeria also kills tumor cells directly. This combination of direct kill and memory T cell based immunogenic kill is enough to effectively remove metastases and guarantee long-term survival. Recently, we received funding from the Pancreatic Cancer Action Network (PCAN) to test this approach of Listeria-RA against pancreatic cancer. We are now testing various RAs in metastatic mouse tumor models of breast and pancreatic cancer, in combination with standard chemotherapy. We showed complete elimination of metastatic pancreatic cancer in an advanced stage (Fig 2, Attachment 1), in correlation with vigorous T cell responses and tumor cell death in the pancreas (Fig 3, Attachment 1).
The central question in the current proposal is whether effective elimination of cancer will extend lifespan. Indeed, were it not for cancer, various highly promising anti-aging approaches, such as rapamycin, resveratrol or metformin, and various other compounds are likely to significantly increase human healthy life span. With the availability of cancer immunotherapy using our Listeria-RA approach that is also effective at old age, we will now be able to use these interventions much more effectively, with gains in life span that could be enormous. To evaluate this approach, we will test our Listeria-RA in female and male BALB/c mice that naturally age and develop spontaneous tumors and metastases. Indeed, metastatic cancer as a cause of natural death during aging is even more common in mice than in humans. First, memory T cells will be generated with the human childhood vaccines to RA in relatively young BALB/c mice when immune responses are still vigorous (12 months of age). Then, we will let the mice age (lifespan of BALB/c mice is 638 +/- 260 days). Once the first spontaneous tumors and metastases occur (17 months)(verified by PET/CT before and after treatment) we will start administering the Listeria-RA and chemotherapy (one cycle every three months until death). At the end of life, when mice become moribund they will be euthanized (time point of death will be used as survival endpoint), and the effect of therapy will be analyzed on tumors and metastases in correlation with survival rates and health. From this data we will determine the median and maximal lifespan. For healthy lifespan, Einstein’s Histo and Comparative Pathology Facility will perform a complete histopathology examination, and The Institute of Aging Research and the Nathan Shock Center of Excellence in the Biology of Aging will perform a complete physical exam. Also T cell responses to the RAs will be analyzed.