# Metabolic Engineering of Bacteria for Cancer Immunotherapy by Gamma Delta T Cells

> **NIH VA I01** · IOWA CITY VA MEDICAL CENTER · 2022 · —

## Abstract

In the United States and throughout the world, cancer incidence and mortality has increased dramatically in
both developed and developing nations. Cancer causes ~13% of human deaths with 7.6 million people dying
from cancer in 2007. More people in the US die of lung cancer than breast, colon, kidney, and prostate cancers
combined. Recent studies show that veterans are 25 to 75 percent more likely to develop lung cancer than
people who did not serve in the military. Advances in cancer immunotherapy are leading to breakthroughs in
treatment. Adoptive transfer of T cells expressing chimeric antigen receptors (CAR-T) results in durable remis-
sions for B cell malignancies. Checkpoint blockade with antibodies against PD-1, PD-L1, and CTLA-4 results in
partial and complete responses in patients with a variety of malignancies. Yet, significant limitations exist. With
the exception of patients with melanoma, only a minority of patients respond to checkpoint blockage. Common
cancers such as prostate and colorectal cancer generally do not respond. Thus, additional approaches are
needed to realize the full potential of cancer immunotherapy.
 Treatment with γδ T cells expressing Vγ2Vδ2 TCRs is one such approach. Unlike αβ T cells, the response
of Vγ2Vδ2 T cells is not MHC restricted but instead requires the Ig superfamily protein, butyrophilin 3A1, to
sense the foreign-microbial isoprenoid metabolite, HMBPP, and the self-metabolite, IPP. This sensing allows
tumor cells to be recognized and killed by Vγ2Vδ2 T cells independent of their mutational burden. Vγ2Vδ2 T
cells safely expand to very high numbers during many infections (up to 1 in 2 circulating T cells) where they kill
infected cells and secrete inflammatory Th1 cytokines, chemokines, and growth factors.
 Two approaches are being used to treat cancer with Vγ2Vδ2 T cells. The first is to immunize with stimula-
tors such as the bromohydrin analog of HMBPP or the aminobisphosphonate zoledronic acid with low-dose IL-
2. Although treatment has resulted in partial remissions, these vaccines eventually cause anergy and deletion
of the Vγ2Vδ2 T cells. The second is to adoptively transfer Vγ2Vδ2 T cells. This approach is safe and has in-
duced complete remissions in three patients with solid tumors, and induced partial remissions or stable dis-
ease in others. However, for widespread adoption, Vγ2Vδ2 T cell therapy needs to be more effective.
 Live bacterial vaccines have been used to prevent tuberculosis, typhoid fever, and tularemia. The bacteria
produce compounds that activate innate immunity and antigens that stimulate αβ T cells to provide help to the
Vγ2Vδ2 T cells as they expand. We have now identified an attenuated Listeria strain that consistently ex-
pands Vγ2Vδ2 T cells. Listeria preferentially accumulate in tumors which should allow the specific tar-
geting of adoptively-transferred Vγ2Vδ2 T cells to tumors as well as TCR stimulation at the tumor site
by HMBPP. We also find that Vγ2Vδ2 T cells rapid...

## Key facts

- **NIH application ID:** 10412920
- **Project number:** 5I01BX000972-11
- **Recipient organization:** IOWA CITY VA MEDICAL CENTER
- **Principal Investigator:** CRAIG T MORITA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-10-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412920

## Citation

> US National Institutes of Health, RePORTER application 10412920, Metabolic Engineering of Bacteria for Cancer Immunotherapy by Gamma Delta T Cells (5I01BX000972-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10412920. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*