Funded Grants

RICS Therapy for Gliomas

Primary malignancies of the central nervous system (CNS), or gliomas, cause the deaths of between twelve thousand and seventeen thousand cancer patients annually. These are among the most lethal of cancers. For instance, breast cancer may strike 10 times as many people in a given year, but still there is an equivalent number of deaths from breast and brain tumors. Malignant gliomas make up the majority of primary brain tumors, and they are the most frequent solid tumor of childhood cancers. Recent evidence also suggests that these tumors are becoming increasingly prevalent among the elderly.

Despite important advances in tumor detection and imaging, and in surgical techniques, treatment of most CNS tumors has been ineffective and the prognosis for these patients remains poor. Gliomas are particularly hard to treat because of their tendency to infiltrate into the folds and tracts of the brain. That is, they develop a central mass of tumor cells, but have many small extensions of tumor cells into the surrounding brain. Surgical procedures are of limited benefit for brain tumors as removal of a generous margin of tissue around the tumor mass is not possible in the brain, as opposed to solid tumors in other sites. In essence, the main part of the tumor can be taken out, but to get the infiltrative elements of the tumor, a large amount of healthy brain tissue would also have to be taken out. This, of course, is not possible, so the tumor ultimately continues to grow because all of it is not removed. Similar concerns limit the usefulness of radiation therapy as specific targeting of the infiltrative elements of tumors presents a significant challenge and the doses of radiation needed to kill tumor cells can also kill normal brain tissues. Chemotherapy can have an impact, but there is significant toxicity associated with its use, and the effects of this type of treatment on infiltrative tumor cells are also limited. At present, an appropriate balance between effective treatments and minimal deleterious effects on brain function can not easily be achieved. Recurrence of the tumor is generally within months and in some disease entities (e.g. glioblastoma multiforme) up to 80% of patients die within a year. While some treatments have shown promise for gliomas, the prognosis for patients with primary brain tumors has not improved significantly in decades.

In practical terms, the next challenge can be simply stated. How can one target and eliminate the infiltrative elements of these tumors to improve therapy? Given the limitations of standard therapies, significant attention has been focused on development of alternative or complementary therapeutic approaches, such as activating the immune system. In the recent past, the CNS was often viewed as being isolated from the immune system, i.e. as being an immunologically privileged or inert site. Some experimental support exists for this view as it was observed that some immune-based therapies, otherwise effective in preventing the systemic recurrence of melanoma, failed to prevent their relapses in the CNS. In fact, several aspects of the CNS may influence immune reactivity in the brain including distinctive anatomic features such as the absence of conventional draining lymphatics and the presence of the blood-brain barrier. However, the immunologic privilege of the brain is far from absolute; and, there is clear evidence of immune responses established in the periphery which manifest in the CNS in autoimmune and tumor models. In truth, there is extensive evidence for the infiltration of gliomas by immune cells; and more importantly, there is evidence for localization of immune cells in the infiltrative elements of gliomas. This has resulted in substantial efforts to use the immune system to treat these tumors; and a number of reports are now available indicating that immunologic approaches to therapy can be of some benefit in the treatment of gliomas.

Gliomas are infiltrated by immune cells such as lymphocytes, but still grow progressively and invasively. Therefore, it is apparent that the tumor infiltrating lymphocytes (TILs) are generally ineffective in mediating anti-tumor functions. There is ample data, including our own, analyzing immune cells sorted from gliomas indicating that their function is suppressed. However, given the recent advances in 1) the understanding of immune suppression and evasion by tumors; 2) use of biological response modifiers (BRMs) to activate lymphocytes in situ; 3) use of activated lymphocytes for adoptive cellular immunotherapy; and 4) development of vaccines for induction of specific anti-tumor immunity, it may prove possible to shift the balance in tumor-bearing individuals towards effective immunity to tumors.

The main hypothesis underlying the proposal I have submitted is that the reversal of immunosuppression coupled with cytotoxic cell stimulation, RICS therapy, will have a therapeutic advantage over either approach as a single therapeutic modality. The approach we are taking combines the most recent and attractive results from various protocols aimed at inducing effective immune responses to gliomas. First, it is clear that gliomas produce transforming growth factor (3 TGFBeta), and this is responsible for much of the immune suppression associated with these tumors. Tumor cells make several forms of TGFBeta but they all bind to a similar receptor on lymphocytes, thereby inhibiting their function. It has recently been shown that blocking the production of TGFBeta by tumors, using an anti-sense oligonucleotide strategy, resulted in less tumor growth and improved immune responses to tumors. Phase I clinical trials based upon this approach are now in progress. However, this approach to blocking TGFBeta production requires that each cell be affected individually; and therefore a large percentage of tumor cells must express the anti-sense oligonucleotides to have significant efficacy. Unfortunately, current techniques for delivery of the anti-sense or its expression in tumor cells in situ only allow a very small percentage of cells to be affected. This will obviously limit the benefit of this technology. Fortunately, elimination of TGFBeta can be improved by making a simple shift in approach. That is, we propose to deliver a soluble receptor for TGFBeta to the tumor that will bind and inactivate this factor. This can be done by delivering a recombinant receptor via intravenous or intra-tumoral injection; or by tumors, and can also be given locally using gene therapy protocols. While this cytokine induces anti-tumor immunity, it is not highly effective as a single therapeutic agent, and large doses of this cytokine have significant toxicity for patients. Because there is promise associated both with elimination of immunosupressive factors made by tumors and with activation of immunity with cytokines, it seems obvious to hypothesize that combining these approaches will provide an improved response. Further, elimination of the immunosuppressive effects using the soluble receptor for TGFBeta will likely reduce the amount of 11,12 necessary to activate cytotoxic cells and thereby reduce or eliminate the toxicity associated with its use. It is my belief that there is great potential for combined approaches, and these will almost surely prove far more effective than any single therapy. In our initial period of developing these approaches, we will focus on combinations of therapy involving the immune system. As has been our approach in the past, we are starting with preclinical modeling with the goal of translating this approach into clinical practice as soon as possible.

Being diagnosed as having a brain tumor can be devastating, and this disease evokes an emotional response in all of us unlike any other disease. Fortunately, through the combined strength of efforts of scientists, clinicians, patients, patient's families, and proactive people from all walks of life, there are exciting and promising approaches which may be translated into improvements in treatment, and hopefully into cures. I can only hope that the results of our work can contribute to some improvement in the treatment of brain tumors. One can not overstate the potential importance of improved therapy for these cancers.