# Immunological approaches to overcoming therapy resistance in human tumors

> **NIH NIH P30** · WISTAR INSTITUTE · 2024 · $749,999

## Abstract

Project Summary
Immune therapy in cancer has made great strides in the past decade. However, not all tumor types benefit from
current therapies. Additionally overcoming resistance to both targeted and immune therapy for second- or third-
line therapies remains a critical challenge for all cancers. Developing experimental models to advance new
immune therapy strategies has faced impediments, hindering progress. Most studies require clinical trials for
even minor advancements in approaches, protocols, timing, dosage, and sequential treatments. Our laboratory
has developed a new experimental model of immune cell-tumor interactions that will fill an important gap in
immune oncology investigations because it is: i) autologous, as immune and tumor cells are derived from the
same patients; and ii) reproducible, as tumor cells and iPS (induced pluripotent stem) cells have unlimited
growth capacities. The source of melanoma cells are the patients’ lesions, which are maintained as PDX (patient-
derived xenografts), organoids, or cell lines. iPS cells are conveniently derived from peripheral blood
mononuclear cells or normal fibroblasts. Three cell types, monocytes, pre-T cells and thymic epithelial cells, are
independently developed from the same iPS cultures. The monocytes are loaded with tumor antigens (tumor
cells, extracts, proteins, or peptides), acting as antigen presenting cells. When the three cell types are placed
together as thymic organoids, the T cells mature and appear stable and can be expanded. The first aim proposes
to investigate T cell receptor diversity and achieving tumor specificity. The second aim characterizes tumor cell-T
cell interactions and how the system can be used to overcome resistance to both checkpoint inhibitors and
targeted therapies. We plan to develop melanoma cell-iPS cell pairs from patients resistant to checkpoint
inhibitors including anti-PD1 and/or CTLA4 and those who are resistant to both targeted and immune checkpoint
therapies. We will then develop complex organoids with stromal and immune cells to mimic tumor-T cell
interactions within an intact microenvironment. Finally, we will transfer the in vitro model to an in vivo setting
using our extensive experience in humanizing mice.
Furthering our on-going collaboration with NCI’s Patient-Derived Models Repository (PDMR) will enable us to
expand the technology and conduct critical research aimed at developing new approaches to overcome therapy
resistance. Moreover, this collaboration will allow for sharing our new models with the scientific community and
extending this innovative approach from melanoma to other malignancies.
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## Key facts

- **NIH application ID:** 11080526
- **Project number:** 3P30CA010815-55S1
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Dario C Altieri
- **Activity code:** P30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $749,999
- **Award type:** 3
- **Project period:** 1997-04-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11080526

## Citation

> US National Institutes of Health, RePORTER application 11080526, Immunological approaches to overcoming therapy resistance in human tumors (3P30CA010815-55S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11080526. Licensed CC0.

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