Lung Cancer Initiating Cells (LCIC) from Malignant Pleural Effusion (MPE) and Dendritic Cells (DC) mediated immunotherapy strategies.
New Faculty II
$1 790 500
According to the Centers for Disease Control, lung cancer accounts for more US-deaths (~170,000) than breast cancer, prostate cancer, and colon cancer combined. Although between 85-90% of all lung cancer deaths are directly attributable to tobacco use, it is not known exactly when and how normal lung cells become malignant. In fact, more lung cancers presently arise in former smokers than in active smokers. We have hypothesized that lung cancers may arise from stem or progenitor cell populations, a concept that dates back at least a quarter of a century. We have spent the last 20 months developing methods to isolate and characterize such cells from clinical specimens, and have identified putative lung cancer initiating cells (LCIC). This proposal seeks to exploit our ongoing effort at LCIC-isolation with a strategy to jointly develop strategies for the treatment of lung cancer. Thus, as we identify cells that possess LCIC properties, we will determine whether there are factors in their tumor-environment that enable these cells to survive, and factors which may impair the immune response of the patient to their tumor. In our experiments, we will seek to neutralize such survival and immune suppressive factors, and determine whether these measures enable us to induce an effective anti-tumor response by vaccinating against lung cancer initiating cells.
Statement of Benefit to California:
The American Cancer Society estimates that lung cancer presently accounts for more California-deaths (~14,500) than breast cancer, prostate cancer, and colon cancer combined. Approximately 15,650 new cases of lung cancer are annually diagnosed among men and women in California. Although the vast majority of these cases are directly attributable to tobacco use, more lung cancers presently arise in former smokers than in active smokers. To develop better targeted and more effective preventative and/or treatment strategies, we first have to develop a better understanding of how lung cancer develops. For the past 20 months, we have embarked on a project that seeks to test the hypothesis whether lung cancers may arise from stem or progenitor cell populations, a concept that dates back at least a quarter of a century. Because we have been able to identify putative lung cancer initiating cells (LCIC) in primary clinical specimens, we want to couple that ongoing effort with an immunotherapeutic strategy against these cells for the treatment of lung cancer. Specifically, as we identify putative LCIC in clinical specimens (Malignant Pleural Effusions or MPE), we will screen their tumor microenvironment (TME) for factors that are jointly LCIC-survival factors and immunomodulatory, which curtail the patient’s anti-tumor immune responses. In this proposal, we have designed approaches to screen and validate the properties of such factors in the MPE-TME, and then to neutralize these factors to measure whether more effective anti-tumor responses can be restored in both in vitro and in vivo models using vaccination approaches against LCIC cells. Upon the completion of our aims, we will have better characterized specific factors in the MPE-TME that sustains LCIC in patients, and whether the neutralization of these specific factors engenders effective immune responses in a novel humanized animal model of lung cancer. The identification of such factors and will enable the development of more effective preventative and treatment strategies for the leading cause of cancer-mortality in the world.
The Principal Investigator (PI) has isolated and characterized cells from clinical specimens of patients with lung cancer. The malignant pleural effusion (MPE) is a good source for cells that have tumorigenic phenotypes including the putative lung cancer initiating cell (LCIC). The applicant proposes that the tumor microenvironment (TME), herein defined as the soluble factors present in the MPE, support the survival of LCIC by promoting cell proliferation and inhibiting the immune response and that inhibition of these factor(s) may lead to a more effective cancer vaccine against LCIC. The PI proposes to identify these factors through proteomics and evaluation of the biological activity on LCIC in vitro and in vivo. The applicant proposes to test in vitro whether improved immune responses against LCIC can be generated by vaccination and by manipulating the TME. This cancer vaccine would then be tested in vivo for anti-tumor activity. The proposed research addresses a potentially important problem in the stem cell field. The idea is that targeting of the LCIC in their microenvironment will lead to a better understanding of and treatment for lung cancer. The idea of cancer stem cell is not new but the approach in this proposal to look at the soluble factors of the microenvironment and their effect on the immune response is innovative. The proposal is well designed and there is supporting preliminary data. However, the reviewers noted several serious weaknesses with the research plan which led them to question its feasibility. All the reviewers found this to be a very ambitious proposal. They thought that the studies to identify soluble factors in the MPE by proteomics and to then determine biological and immuno-modulatory effects on LCIC to be the weakest part of this proposal. These studies are difficult, expensive, time consuming and highly risky. At the end of proteomics studies, the investigator can have large amounts of data that can be very difficult to interpret. One reviewer noted that combinations of factors may be important for activity and that the PI had not addressed this consideration. This is a potential pitfall and as noted by another reviewer, the pitfalls section is very weak with no significant alternatives proposed. The reviewers expressed concern that success of the proposed in vivo vaccination studies will likely rest on being able to purify the LCICs to sufficient purity to elicit an immune response. Commonly the most highly purified cancer stem cells constitute only a few percent of the total tumor cell population. It’s not clear how significantly enriched LCICs will be isolated for these studies. Overall the reviewers considered the Ideas good but the plan for execution seriously deficient. The applicant has a good publication record, the last two in 2006 and including publications in noted journals. The PI’s expertise in immunology and vaccine production is clear from his/her publications but there is as yet no publication in cancer stem cells or the stem cell arena. She/he currently has an internal grant. The PI’s career development plan is reasonable and the milestones are realistic. His/her mentors have appropriate qualifications and their roles are clearly defined. The mentors are quite good and there is a plan for weekly meetings and joint lab meetings. Both of the mentors plan to devote 10% of their time to the PI’s career development. The reviewers noted that the institution’s commitment to the candidate’s career, including laboratory space, salary and research support was weak. They particularly noted that the institution was providing no salary support that would enable the PI to carry out the research. There was no information about how the stem cell institute will be able to uniquely promote the development of this applicant or other budding scientists. The reviewers also expressed concerned that there was no real plan for the applicant to be part of a stem cell program thus impacting his/her potential for leadership in the stem cell field. Thus although the reviewers consider the future of this PI in science to be good, they consider it less likely that she/he will become a leader in the stem cell field.