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FINDING CURES TOGETHER<sup>SM</sup>

The 2018 Phillip A. Sharp Awards for Innovation in Collaboration

Cupid-seq: high throughput transcriptomic spatial mapping of micro-environment immune-tumor interactions

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Dan Landau, MD, PhD, Joan and Sanford I. Weill Medical College

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Raul Rabadan, PhD, Columbia University

Grant Term: July 2018 - June 2020
Total Funding: $250,000

Project Summary
The development and progression of cancer is the result of the interplay of genetic characteristics of the tumor cells, and the complex interactions of the cancer cells with the different cells in the tumor microenvironment. Single-cell RNA-sequencing has been used to study the different cells in the microenvironment. Unfortunately, the interaction between the different cells (cancer and non-cancer) cannot be fully studied since tumor tissue samples are generally broken down prior to analyses. The co-leaders have proposed a novel single-cell RNA sequencing methodology which they call Cupid-seq. With Cupid-seq, the tissue samples are not dissociated completely. This enables scientists to sort and analyze cell doublets, e.g. tumor-immune doublets or immune-immune doublets.

Accomplishments
The team developed a methodology to correctly classify doublets and singlets into their constituent cell types with 99.5 percent accuracy.

Characterizing immune-variability in children following standard of care treatment to enable precision assignment to immunotherapy trials

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Trevor J. Pugh, PhD, University Health Network

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David M. Barrett, MD, Children's Hospital of Philadelphia

Grant Term: June 2018 - May 2019
Total Funding: $250,000

Project Summary
Not all pediatric cancer patients can be enrolled on pediatric immunotherapy trials. Unfortunately, the immune cells of pediatric cancer patients, and the patients themselves, are weakened by the prolonged chemotherapy that is used to treat these patients. The team wants to understand the effect of standard pediatric cancer care on children's immune T cells. 

Accomplishments
The team has recruited 48 patients, who have different pediatric cancer types. They will analyze the T cells in these patients and relate the characteristics of these T cells to response to chemoradiation (whether the patient responded or whether they experienced toxicity) and to any future immunotherapy.

Interrogating impact of epigenetic modifiers on durable reprogramming of exhausted CD8 T cells in patients with NSCLC

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Matthew Hellman, MD, Memorial Sloan Kettering Cancer Center

Grant Term: May 2018 - April 2020
Total Funding: $250,000

Project Summary
Cancer-killing T cells can also be "exhausted." This occurs after they have been interacting with cancer cells for an extended period of time. Immune checkpoint antibodies can reinvigorate these exhausted cancer-killing T cells (TEX). It has been found that TEX have differences in the modifications in their DNA (called epigenetic modifications). Unfortunately, it has been found that PD-1 blockade alone cannot alter this DNA modification pattern -- TEX are transiently reinvigorated by PD-1 blockade but the cells quickly revert to an exhausted dysfunctional state. The team hypothesizes that combining epigenetic drugs with anti-PD-1 can improve TEX reinvigoration compared to anti-PD-1 alone. 

Accomplishments
The team has begun analyses on blood samples from nine patients treated with anti-PD-1 +/- epigenetic drugs.

Studies of colorectal cancer patient-derived organoids to validate candidate biomarkers of resistance to natural killer cells

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Michal Sheffer, PhD, Dana-Farber Cancer Institute

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Hugo J. Snippert, MD, Utrecht University

Grant Term: June 2018 - May 2020
Total Funding: $250,000

Project Summary
Aside from cancer-killing T cells, our bodies have other immune cell types that can potentially attack cancer cells. One of these immune cell types is called the natural killer cell (NK cell). It has been observed that cancer cells have genetic characteristics that may protect them from the attack of NK cells. The team plans to validate the importance of these genetic characteristics in colorectal cancer (CRC) organoids. An organoid is a kind of 3D cell culture. 

Accomplishments
The team has developed a laboratory method to assess the sensitivity of their CRC organoid cultures to NK cells. Given that genetic data on these organoid cultures is or will be available, the team expects to be able to correlate genetic characteristics of these cultures with NK cell responsiveness. 

Aptamer-based Detection and Binding of Peptide-MHC

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Cassian Yee, MD, MD Anderson Cancer Center

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Bruce Sullenger, PhD, Duke University Medical Center

Grant Term: May 2018 - April 2019
Total Funding: $250,000

Project Summary
There is a need to more accurately assess the relationship between proteins in the surfaces of cancer cells, and the ability of the cells in the immune system to present fragments of these surface proteins (called peptides) to the cancer-killing T cells. Major histocompatibility complexes (MHC) on immune cells are responsible for holding on to the peptides in such a way that T cells can recognize the peptides, and kill the tumor cells that contain the proteins from which these peptides came. Nucleic acid tools, called aptamers, can be used to study specific peptide-MHC complexes on tumor and non-tumor cells. 

Accomplishments
The team has begun to select aptamers which can recognize the peptide fragment from the protein called NY-ESO-1.