The immune system is very powerful. It can precisely target pathogens and attack them with high eﬃciency. Most infections last a few days, or at most weeks, and then are permanently eliminated with little or no damage to the body. In contrast cancer can last many years and often results in death. Cancer will aﬀect one in three of us. Many treatments for cancer have been developed, but are often of limited eﬃcacy and have harsh side eﬀects. Therefore, it would be a major breakthrough in cancer therapy if the power and precision of the immune system could be brought to bear against cancer.
Most eﬀorts to treat cancer with immunotherapy have involved vaccines. Some vaccines have had success, many have failed. Another, more recently developed treatment is that of T cell reprogramming. In this approach, T cells are taken from a patient, genetically modiﬁed to express antibodies against a novel antigen, and then infused intravenously back into the patient. The use of autologous T cells prevents graft-‐vs-‐host disease, while the genetic modiﬁcation makes the T cells target the cancerous cells, and the fact that the T cells are exogenously cultured means that the treatment does not depend upon the patient to generate a strong immune response.
The genomically informed choice of antigen makes it applicable to a wide variety of cancers and makes personalized medicine a reality. To make T cell reprogramming more eﬀective for general use, two modiﬁcations must be made. First, the antigen to target must be carefully chosen. Whole genome sequencing of tumor cells would reveal any cell surface proteins that have undergone mutations. The most promising candidate can be chosen as a target antigen. Intra-‐tumor heterogeneity may make it necessary to target multiple antigens. Then T cells can be reprogrammed to target the target antigen(s).
Second, the cancer must be diligently monitored and additional antigens selected for targeting if the initial antigen is lost. Fortunately, advances in genome sequencing make both of these modiﬁcations possible. Ideally, the cancer would be completely eradicated by the T cell therapy. However, it is possible that some cancer cells might survive. If this is the case, then the surviving cells must be monitored. If there is evidence that the targeted antigen has been lost, then new target antigens must be chosen and a subsequent round of T cell therapy undergone.
This project will involve various kinds of research, sequencing the cancer cells, bioinformatic analysis of sequence data, generating antibodies against candidate antigens, taking T cells, personalized reprogramming of T cells, infusion and monitoring of mouse health, with the possibility of subsequent rounds of treatment. Initially, a pilot study can be done, leading to a larger study in order to establish efficacy.
Monitor for cancer, perform biopsies, sequence, generate T cells, infuse T cells and monitor health, with sequencing of surviving cancer cells once every 3 months.
Staﬀ salaries: $440,000/year.
Research materials: $20,000/year
Equipment (hoods, etc.): $250,000
3 specialists, 3 scientists, 2 bioinformaticians, 3 technicians.
Staﬀ salaries: $760,000/year
Research materials: $100,000/year
One-‐oﬀ expenses: Computers: $105,000
Equipment (PCR machines, tissue culture hoods etc.): $850,000
Project total: $2,592,500