Adoptive T Cell Therapy

Adoptive T cell therapy involves the isolation and ex vivo expansion of tumor specific T cells to achieve greater number of T cells than what could be obtained by vaccination alone.  The tumor specific T cells are then infused into patients with cancer in an attempt to give their immune system the ability to overwhelm remaining tumor via T cells which can attack and kill cancer.  There are many forms of adoptive T cell therapy being used for cancer treatment; culturing tumor infiltrating lymphocytes or TIL, isolating and expanding one particular T cell or clone, and even using T cells that have been engineered to potently recognize and attack tumors.  Our approach has been to utilize T cells taken directly from the patient’s blood after they have received a cancer vaccine.  We have found by “priming” rare tumor antigen specific T cells first, with active immunization, we are much more able to expand those T cells in the laboratory to greater numbers for therapeutic infusion.

A unique aspect to our approach for adoptive T cell therapy is the use of tumor specific CD4+ Th1 cells which may enhance anti-tumor efficacy.  Adoptive T cell therapy strategies have largely focused on the infusion of tumor antigen specific cytotoxic T cells (CTL) which can directly kill tumor cells.  However, CD4+ Th cells have a broader functionality.  Th can activate antigen-specific effector cells and recruit cells of the innate immune system such as macrophages and dendritic cells to assist in antigen presentation (APC).  Moreover, antigen primed Th cells can directly activate tumor antigen-specific CTL.  In addition to direct contact, Th can activate CTL through cytokines such as IL-2 which stimulate the growth and expansion of effector T cells.  In addition, Th1 induce the production of opsonizing antibodies that enhance the uptake of tumor cells into APC.  These activated APC can then directly present tumor antigens to T cells.

As a direct result of activating APC, antigen specific Th1 have been implicated as the initiators of epitope or determinant spreading which is a broadening of immunity to other antigens in the tumor.  The phenomenon of epitope spreading has been linked with a survival benefit after immunotherapy in patients with melanoma and breast cancer.  The ability to elicit epitope spreading broadens the immune response to many potential antigens in the tumor and presumably would result in more efficient tumor cell kill due to the ability to mount a heterogeneic response.  In this way, adoptive T cell therapy can used to stimulate endogenous immunity.

T cell Therapy from Laboratory to Clinic

  • We developed novel methods to expand CD4 Th1 cells in culture in a way that would be suitable for clinical infusion using cytokines that preferentially elicit the outgrowth of Th1 cells (Dang et al CCR, 2006).
  • Studies by our group have demonstrated that tumor antigen specific T cells can be easily expanded ex vivo after vaccination.  Indeed, the magnitude of the T cell response achieved after vaccination will predict the ability to expand tumor specific T cells to greater numbers (Dang et al, CCR, 2006).
  • We have initiated Phase I and II clinical trials of adoptive T cells therapy in breast cancer after HER2 vaccination.  Early studies have demonstrated that infusion of competent T cells result in a magnitude of tumor antigen specific immunity more than a log higher that what can be achieved with immunization.
  • In advanced stage breast cancer patients, infused antigen specific T cells can persist and even augment in vivo as long as a year after infusion.  The treatment is associated with few side effects.
  • We have ongoing Phase I and II clinical trials in a variety of cancer types.

Future Directions

We continue to evaluate the role of adoptive T cell therapy for the treatment of advanced stage cancers.  In addition, we are focusing on methods to expand T cells more readily in culture by developing new immunization regimens as well as developing novel culture systems.  We are evaluating ways to change the phenotype of the T cell generated to make those cells more effective in killing cancer cells.  Finally, we are assessing methods to enhance the ability of the T cell to better penetrate the tumor, thereby allowing greater numbers of the destructive T cells to migrate deep into the tumor and cause the death of malignant cells.  In combination with this line of investigation we are working with collaborators to develop novel methods to label and track tumor specific T cells in vivo on both animal models and patients.  The ability to visualize T cells homing to tumor will allow us to optimize therapeutic efficacy of the approach.