At its foundation, ACT involves isolating lymphocytes with high affinity for a particular antigen, expanding those cells in vitro to produce a greater quantity of reactive cells, and infusing the product cells into patients to attack cells expressing the antigen, such as tumor cells, bacterial cells, or viral particles. Previously utilized ACT procedures have been plagued by technical, regulatory, and logistical problems that have prevented consistently successful clinical outcomes. Through years of research, scientists at the National Institutes of Health (NIH) have made great strides in developing ACT into a viable approach to treat cancer patients. Of note, the ACT protocols developed by NIH scientists have successfully treated patients with refractory metastatic melanoma who started with very few effective treatment options. These NIH scientists have found that isolating cells from the tumor infiltrating lymphocytes (TIL) of a patient tumor sample provides a suitable initial lymphocyte culture for further in vitro manipulations. They have also discovered that taking the isolated cells through one cycle of rapid expansion (including exposure to IL-2), rather than multiple cycles, yields lymphocyte cultures with higher affinity and longer persistence in patients. Also, they have found that administering nonmyeloablative lymphodepleting chemotherapy prior to the reinfusion of lymphocytes creates a more favorable environment within patients for the transferred cells to execute target cell killing. These scientists envision that, for an ACT immunotherapy to gain regulatory approval and successfully treat a wide array of patients, it will need to be rapid, reliable, and technically simple. One of the most critical factors to this approach is the generation of effective lymphocyte cultures that will rapidly and repeatedly attack the target cells when infused into patients.

Scientists at the NIH have developed a method of generating CD8+ selected “young” lymphocyte cultures for infusion into cancer patients. Lymphocytes that spend fewer days in vitro between their initial isolation from TIL and their ultimate reinfusion into patients compared to lymphocytes cultured by previous ACT protocols are considered young lymphocyte cultures. Young lymphocytes, typically 19-35 days old when reinfused into patients, exhibit improved proliferation, survival, and enhanced anti-tumor activity within patients to yield greater tumor regression compared to older lymphocytes, typically 44+ days old. Furthermore, the generation of young lymphocyte cultures is more rapid, reliable, and technically easier than previous ACT culturing methods. Young lymphocytes are isolated from TIL, directed against a single isolated tumor cell suspension, enriched for CD8 expression, and rapidly expanded once using autologous feeder cells without testing the culture for antigen specificity.

This approach to ACT offers a potentially significant improvement and a valuable new immunotherapeutic tool for attacking tumors. For diseases, such as metastatic melanoma, where patients may only have weeks or months of life expectancy, this technology, which provides for improved cell cultures prepared in less time, can make a difference between life and death. In addition, this method might be applicable in treating other diseases such as AIDS, immunodeficiency, or other autoimmunity for which immune effector cells can impact the clinical outcome.

Advantages:

• Technically simpler than previous ACT methods: Decreased number of steps in the procedure and less analysis of the cell cultures prior to reinfusion into patients.

• More rapid than previous ACT methods: Adoptively transferred lymphocytes spend fewer days undergoing in vitro culturing, so they are introduced to patients with potentially short life expectancies more quickly.

• Reliable, life-saving technology: This technology is anticipated by the inventors to yield greater tumor regression and more objective clinical responses in patients compared to previous ACT protocols and all previously attempted treatments for metastatic melanoma.

Development Status: This technology is being utilized in a clinical protocol for adoptive cell transfer. The technology is a critical component of the successful immunotherapy regimen being used by the inventors and other clinicians at the NCI. Patients enrolled in ACT protocols are expected to show enhanced tumor regression and more objective responses compared to results obtained with previous protocols.

Market: Cancer continues to be a medical and financial burden on US public health. According to US estimates, cancer is the second leading cause of death with over 565,000 deaths reported in 2008 and almost 1.5 million new cases were reported (excluding some skin cancers) in 2008. In 2007, the NIH estimated that the overall cost of cancer was $219.2 billion dollars and $89 billion went to direct medical costs. Despite our increasing knowledge of oncology and cancer treatment methods, the fight against cancer will continue to benefit from the development of new therapeutics aimed at treating individual patients.

A technically simpler, more rapid, more clinically reliable ACT procedure with greater potential to overcome the technical, regulatory, and logistical hurdles of past ACT methods. This technology could be broadly transferrable to a wide array of institutions to treat a wide array of patients.

The immunotherapy component of a combination therapy regimen aimed at targeting the specific tumor-associated antigens expressed by the cancer cells of individual patients.

Collaborative Research Opportunity: The Center for Cancer Research, Surgery Branch, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize cell and gene therapy technologies, and personalized medicines. Please contact John D. Hewes, Ph.D. at 301-435-3121 or hewesj@mail.nih.gov for more information.