Background:

The immune system is very powerful. It can precisely target pathogens and aFack them with high efficiency. Most infec.ons last a few days, or at most weeks, and then are permanently eliminated with liFle or no damage to the body. In contrast cancer can last many years and oPen results in death. Cancer will affect one in three of us. Many treatments for cancer have been developed, but are oPen 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 pa.ent, gene.cally modified to express an.bodies against a novel an.gen, and then infused intravenously back into the pa.ent. The use of autologous T cells prevents graP-­‐vs-­‐host disease, while the gene.c modifica.on 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 pa.ent to generate a strong immune response.

Approach:

The genomically informed choice of an.gen makes it applicable to a wide variety of cancers and makes personalized medicine a reality. To make T cell reprogramming more effec.ve for general use, two modifica.ons must be made. First, the an.gen to target must be carefully chosen. Whole-­‐exome sequencing of tumor cells would reveal any cell-­‐surface proteins that have undergone muta.ons. The most promising candidate can be chosen as a target an.gen. Intra-­‐tumor heterogeneity may make it necessary to target mul.ple an.gens. Then T cells can be reprogrammed to target the target an.gen(s).

Second, the cancer must be diligently monitored and addi.onal an.gens selected for targe.ng if the ini.al an.gen is lost. Fortunately, advances in genome sequencing make both of these modifica.ons 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 an.gen has been lost, then new target an.gens must be chosen and a subsequent round of T cell therapy undergone.

Requirements:

This project will involve various kinds of research, sequencing the cancer cells, bioinforma.c analysis of sequence data, genera.ng an.bodies against candidate an.gens, taking T cells, personalized reprogramming of T cells, infusion and monitoring of mouse health, with the possibility of subsequent rounds of treatment. Ini.ally, a pilot study could be done; ul.mately, a larger study, would be necessary to establish efficacy.

Es1mated costs:

Pilot project:
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.
Sequencing: $60,000/year
Research materials: $20,000/year
Reagents: $100,000/year
One-­‐off expenses:
Computers: $75,000
Equipment (hoods, etc.): $250,000

Larger study:

3 specialists, 3 scien.sts, 2 bioinforma.cians, 3 technicians.

Staff salaries: $760,000/year
Research materials: $100,000/year
Reagents: $300,000/year
Sequencing: $100,000/year
One-­‐off expenses: Computers: $105,000
Equipment (PCR machines, .ssue culture hoods etc.): $850,000

Project total: $2,592,500