# Development of Physiologic Tissue Models to Assess Tumor Explant Response to Immune Checkpoint Blockade

> **NIH NIH U01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $676,329

## Abstract

PROJECT SUMMARY
 The goal of this research project proposal is to develop a physiologic model of ex vivo tumor culture to
study responsiveness to immune checkpoint blockade. Although inhibitors of the PD-1/PD-L1 and CTLA4
immune checkpoints have led to remarkable and durable responses in cancers such as malignant melanoma,
the ability to predict the activity for individual patients remains limited, and have relied on measurements from
fixed tumor tissue. While the ability to grow patient derived tumors in organoid models, for example, has been
rigorously demonstrated over the past several years, these systems lack key features of the tumor
microenvironment, including a vascular network and immune cells. Thus, an ex vivo system that supports
tumor and immune cell culture by recapitulating a physiologic microenvironment will almost certainly be
essential to the development of functional assays that can predict patient response to immunotherapy.
 Recently, we demonstrated that our three-dimensional microfluidic culture system can support growth
of primary human tumor spheroids derived from multiple different cancer types, including melanoma.
Importantly, immune profiling of the cells within the spheroids reveals that they also contain a significant
proportion of tumor associated immune cells, including macrophages, dendritic cells, and antigen experienced
T lymphocytes. Exposure of these short term spheroid cultures to immune checkpoint inhibitors such as anti-
PD1 antibodies results in evidence of immunologic response and robust cytokine secretion into conditioned
medium, as well as evidence of cell killing in some cases.
 The broad, long term objective of this proposal is to extend this preliminary model to leverage the
capabilities developed in our labs to incorporate a microcirculatory network in the 3D matrix surrounding the
tumor and use this as a means of subsequently introducing selected myeloid cells. Both the initial model and
these extensions to it will be subject to detailed validation in order to develop a realistic physiologic culture
system that enables prediction of immunotherapy response. A unique aspect of this work is that it spans basic
and translational research, including the use of animal models to help engineer vascularized networks, and
patient-derived samples and clinical response to immune checkpoint blockade to validate the system. Specific
aims are to: 1) Refine and validate an existing microfluidic tumor culture model to assess response to immune
checkpoint inhibitor therapies 2) Incorporate vascular flow of immune cells to monitor extravasation and
expansion of immune effector cells in tumor culture, and 3) Directly compare ex vivo experiments with patient
specific response to immune checkpoint blockade. Through these complementary studies, the ultimate goal is
to develop a robust model that can eventually be adapted to clinical use to help target immune checkpoint
inhibitor therapies to the appropriate subgroup of pat...

## Key facts

- **NIH application ID:** 9999459
- **Project number:** 5U01CA214381-04
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** David A Barbie
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $676,329
- **Award type:** 5
- **Project period:** 2017-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999459

## Citation

> US National Institutes of Health, RePORTER application 9999459, Development of Physiologic Tissue Models to Assess Tumor Explant Response to Immune Checkpoint Blockade (5U01CA214381-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9999459. Licensed CC0.

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