The paper reviews the most recent advances in the field of adoptive immunotherapy of cancer, a procedure consisting of the generation and expansion of anti-tumor immune cells ex vivo prior to their transfer into the tumor-bearing host.

“The paper reviews the most recent advances in the field of adoptive immunotherapy of cancer, a procedure consisting of the generation and expansion of anti-tumor immune cells ex vivo prior to their transfer into the tumor bearing host.”

Adoptive transfer of tumor-specific T cells has emerged as the most potent treatment for patients affected by metastatic melanoma refractory to standard treatments including chemotherapy, radiation, and cytokine therapies. There is high expectation that such a strategy might be applied with success to common malignancies including lung, breast, and colon cancer.

  Does it describe a new discovery or a new methodology that’s useful to others?

In this review paper we elucidate the biology of adoptive cell transfer-based immunotherapies. We describe the importance of eliminating the negative influences of immune cells such as regulatory T cells, cellular "sinks" for activating cytokines, and myeloid suppressor cells prior to the transfer.

We also review recent evidence that indicates that the quality most associated with the effectiveness of T cells is their "youth," specifically their lack of terminal differentiation into cytotoxic T cells. Finally, we discuss how these new findings might guide the rational design of the next generation of adoptive cell-based therapies.

  Could you summarize the significance of your paper in layman’s terms?

This paper describes the biology behind two counter-intuitive findings: 1) the elimination the host’s immune system augments immunotherapy, and 2) highly differentiated cytotoxic T cells are less effective in mediating tumor regression compared to younger non-cytolytic T cells.

  How did you become involved in this research and were there successes or failures?

The prospect of employing a patient’s immune system to treat cancer has been the source of much hope and promise. Initially, we were primarily driven by the goal of developing a therapeutic cancer vaccine. However, like other workers in the field of tumor immunology, we have been unsuccessful in creating therapeutic cancer vaccines that are effective in more than a small minority of patients treated.

In our cancer vaccine trials of 440 patients, we have observed a disappointing 2.6% of objective response rate. We do not know the reasons for this lack of efficacy but cancer vaccines might be limited by the low frequencies of tumor-specific T cells and perhaps, more importantly, by the presence of many redundant negative influences of the host immune system and tumor microenvironment.

These hurdles, however, can be overcome by the use of adoptive cell-based immunotherapies. T cells can be expanded to large numbers and selected for tumor reactivity ex vivo. More importantly, adoptive cell-based therapies allow for manipulating the host before cell transfer to alter the environment without harming the tumor reactive immune cells.

  Where do you see your research leading in the future?

Tumor-specific T cells can rarely be raised from tumor histologies other than melanoma. Therefore, our work will be focused on imparting tumor specificity to open repertoire peripheral blood lymphocytes through a gene engineering approach.

Tumor reactivity can be conferred to non-reactive T cells by using retroviral vectors encoding tumor-specific T cell receptors (TCR), or chimeric receptors with antibody specificity (T-bodies). This strategy not only permits treatment of patients with any malignancy for which a tumor-specific TCR can be cloned, but it also offers the opportunity to select or induce T cells with the best anti-tumor function.

In addition, we are currently developing stronger and more selective approaches to lymphodepletion aimed at eliminating the toxicities associated with the use of non-specific preconditioning regimens based on chemotherapy and radiation.

  Are there any social or political implications of your research?

The development of effective anti-tumor therapies can have significant social impact. Cancer is one of the leading causes of mortality in western countries. In addition, adoptive immunotherapy might be used in the future for the treatment of chronic infectious diseases.