# Stem Cell Biology, Cancer Stem Cell Biology, and Cancer Immunotherapy

> **NIH NIH R35** · STANFORD UNIVERSITY · 2023 · $1,000,669

## Abstract

Summary: This grant application continues my previous work, focusing on integrating stem cell biology,
cancer stem cells and immunology to understand: i) mechanisms controlling stem cell numbers, self-renewal
and differentiation; ii) the genetic/epigenetic `events' that drive cancer initiation and progression through clonal
expansion and competition of stem cells; iii) mechanisms of programmed cell removal of precancerous cells by
macrophage phagocytosis and how cancer cells evade those, and iv) developing innate system [mainly
macrophage-based] cancer immunotherapies.
I was awarded an NCI OIG 28 years ago and used the funding to develop the first method to identify and
isolate blood forming stem cells [HSC]. We applied this discovery in a clinical trial where autologous
transplantation of purified, cancer-free HSC from mobilized peripheral blood [MPB] to metastatic breast cancer
patients following high dose chemotherapy, resulted in 33% 18-20 year survival compared to 7% with MPB.
We then mapped the differentiation steps from stem cells to all mature blood cells and in the context of myeloid
leukemogenesis, studied how genetic alterations modify the affected stem cells. We isolated leukemic stem
cells[LSC] that could regenerate myelogenous leukemia and found that these cells were not phenotypic HSC
but downstream MPP progenitors. Although many HSC in the same patients had the cancer-initiating
mutations, they were not leukemic! Additional mutations or `events' were required, each promoting clonal
expansion and competition of the preleukemic HSC over normal HSC. This model of sequential progression of
events accruing one at a time in HSC `clones' until the LSC emerges holds true for all myeloid leukemias and
preleukemias. Comparing LSC to HSC we discovered that the expression of CD47, a `don't eat me' signal for
macrophage scavenger cells, was a late event for all cancers including leukemias. We made blocking
antibodies to CD47, and found that these led to tumor cell phagocytosis and cancer regression and often cures
in xenograft models of human leukemias and solid tumors. Anti-CD47 antibody synergizes with all other anti-
cancer antibodies tested to date. The current proposal expands on these studies to test whether accumulation
of mutations also occurs in a central nervous system stem cell(CNS SC) clone that gives rise to a brain cancer
stem cell [CSC]. The gene expression profiles of cells from these precancers and cancers should identify new
therapeutic targets. Importantly, normal C47+ cells aren't eaten when CD47 is blocked, because they lack a
pro-phagocytic `eat me signal', calreticulin, that is on all cancers. We will study how cancer cells are labeled
with calreticulin for elimination by macrophages, and extend our macrophage phagocytosis studies to try to
understand how macrophages get rid of old, damaged, and dying cells, and how pathogenic stem cells avoid
being eaten via CD47 or other `don't eat me' signals. In these studies we will...

## Key facts

- **NIH application ID:** 10693077
- **Project number:** 5R35CA220434-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** IRVING L. WEISSMAN
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,000,669
- **Award type:** 5
- **Project period:** 2017-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693077

## Citation

> US National Institutes of Health, RePORTER application 10693077, Stem Cell Biology, Cancer Stem Cell Biology, and Cancer Immunotherapy (5R35CA220434-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10693077. Licensed CC0.

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