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Kure It-AACR Research Grants

The Kure It-AACR Research Grants represent a joint effort to promote and support innovative cancer research. AACR has awarded two grants through this partnership: the Kure It-AACR Grant for Kidney Cancer Research, intended for independent investigators to develop and study new ideas and approaches that have direct application and relevance to kidney cancer patients; and the Kure It-AACR Research Grant for Immunotherapy in Kidney Cancer, available to independent investigators to study immunological aspects of, or treatments for, kidney cancer. Applications are invited from researchers currently in their field as well as from investigators with experience in other areas of cancer research who have promising ideas or research approaches that can be applied to kidney cancer research. These grants support innovative research projects designed to improve the survival and quality of life of patients with kidney cancer and lead to individualized therapeutic options for treatment or the development of promising new cancer therapeutics for kidney cancer.

2016 Grantee

Kure It-AACR Research Grant for Immunotherapy in Kidney Cancer  

Anna Meseguer, PhD 
Head, Renal Physiopathology Group
Vall D'Hebron University Hospital Research Institute
Barcelona, Spain
Could TIM-1 constitute a new target for renal carcinoma immunotherapy? 

Tumor cells and tumor-infiltrating lymphocytes adopt strategies to evade antitumor processes and may enhance the metastatic potential through the activation of chronic inflammatory signals. In the last years the blockade of immune checkpoints has emerged as one of the most encouraging approaches to trigger therapeutic antitumor immunity. Metastatic renal cell carcinoma RCC is one of the cancers where the new immunotherapy approach is generating more expectations and hope. For instance, treatment with agents able to block the interaction of the PDL1 with PD-1 produced durable responses in ~30% of patients with ccRCC. Unfortunately, an important limitation of those treatments is the fairly small proportion of patients who achieve clinical responses. In this context, the search for new immune checkpoints appears to be a necessity in order to increase the number of patients that could benefit of immunotherapy treatments.

We have recently elucidated some of the mechanisms that drive tumor growth and progression by TIM-1 receptor expression in ccRCC and observed a significant correlation between tumor malignancy and invasiveness with augmented TIM-1 ectodomain shedding, both in ccRCC patients and in ccRCC derived cell lines. We have also reported that ccRCC tumors overexpressing TIM-1 become engaged in the expression of a repertoire of molecules that favor tumor growth, apoptosis inhibition, angiogenesis, invasion and immune evasion. TIM-1 ectodomain shedding favors transcription of IL-6 and IL-11, and promotes further activation of the gp130/STAT3 pathway, by mechanisms that remain to be described both in tumor and in surrounding immune cells. TIM-1 is unique in being expressed in ccRCC cells and also in activated T lymphocytes, where seems to constitute a dual receptor, able to deliver both co-stimulatory and negative signals that leads to the activation or inhibition of T-cell effector function, respectively. 

To date, nobody has addressed the issue on how ccRCC cells and the immune system interact through TIM-1, nor envisioned how identification of those mechanisms might provide with novel therapeutic targets. This project aims to study the mechanism through which TIM-1 shedding promotes transcription of relevant targets in tumor cells, and also to identify how the shed ectodomain promotes a cross-talk between the tumor and the host immune system, to further improve our knowledge on ccRCC tumor biology and provide with novel targets for effective and personalized treatment of ccRCC patients. As mentioned, metastatic renal cell carcinoma is one of the cancers where the new immunotherapy approach is generating more expectations but not all patients benefit from current therapies. It is of upmost importance to identify new avenues for the treatment of this devastating disease.

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2015 Grantee

Kure It-AACR Research Grant for Immunotherapy in Kidney Cancer 

Eliezer M. Van Allen, MD
Assistant Professor
Dana-Farber Cancer Institute
Boston, Massachusetts
Response predictors to PD-1/PD-L1 inhibitors in renal cell carcinoma

Checkpoint inhibition with programmed cell death-1 (PD-1) receptor inhibitors and inhibitors of its major inducible ligand, PD-L1, have shown significant promise in early phase clinical trials for patients with metastatic renal cell carcinoma (mRCC). While immunohistochemistry (IHC) testing for PD-L1 may partially correlate with treatment response, patients that stain PD-L1 negative can still respond, and the mechanistic underpinnings of differential treatment response to PD-1/PD-L1 inhibitors are incompletely characterized. The discovery of response effectors to these emerging immunotherapies may greatly impact patient selection, trial design, and therapeutic development for mRCC and other cancer types. This proposal intends to explore the genomic foundation driving response to PD-1/PD-L1 inhibitors in metastatic RCC, along with assessing candidate serum biomarkers. The overarching goals of this proposal are to 1) develop and apply computational biology algorithms that systematically interrogate hypothesized genomic response effectors to PD-1/PD-L1 inhibitors in mRCC and 2) to determine whether hypothesized metabolite predictive biomarkers for PD-1/PD-L1 inhibitor response correlate with clinical response. First, we will perform whole exome and transcriptome sequencing on tumors from a prospective cohort of mRCC patients treated with PD-1 or PD-L1 inhibitors in clinical trials. We will develop and apply novel computational algorithms to systematically explore hypothesized genomic predictors of response in these patients. In our second aim, we will evaluate the predictive capacity of plasma metabolite biomarkers for PD-1/PD-L1 response in mRCC using plasma obtained prospectively from these patients. The ability to define the genomic basis for response to PD-1/PD-L1 inhibitors and prospectively identify patients who are most likely to benefit from these agents with a plasma-based assay may improve patient outcomes and potentially change oncologic clinical practice. Broadly, this proposal may advance knowledge about RCC immunological therapeutic manipulation, and perhaps other malignancies.

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