Projects per year
Project Details
Description
PROJECT SUMMARY/ABSTRACT
Immune effector cells (IECs) targeting tumor associated antigens, such as with chimeric antigen receptors
(CARs) and bi- and tri- specific antibodies, offer unprecedented results in patients previously considered
incurable. The number of cellular immunotherapies for solid tumors and hematological malignancies has
dramatically increased. CAR T cells are now being considered early in the patient’s treatment plan as in children
with CD19+ acute lymphocytic leukemia (ALL), no longer reserved for salvage therapy. However, as experience
grows, a number of issues need to be addressed urgently. The grand challenges of adoptive IEC therapy include:
on-target/off-tumor toxicities, T cell exhaustion, tumor escape by antigen loss, immunosuppressive tumor
microenvironment, variable persistence, and time and cost of individualized product manufacture, limiting global
access. To this end, there are 5 important research themes woven throughout the 3 Projects and 4 Cores,
specifically, 1) the need for safe and effective allogeneic off-the-shelf IECs, 2) IECs that can target multiple tumor
antigens to minimize tumor escape, 3) development of drug regulatable CARs for greater control, limiting on-
target/off-tumor adverse effects and T cell exhaustion, 4) more selective cytokine stimulation to enhance IEC
persistence and potency with minimal systemic side effects, and 5) translation of new engineering methods for
industrial-scale manufacturing. During the current funding period, there have been key discoveries that will drive
the next 5 years of this grant, specifically: the finding that (a) Tregs are effective cancer IECs which can be
engineered to effectively target and kill cancer comparable to conventional T cells, (b) ability to generate iPSC-
derived CD8 iTregs as a renewable starting cell source, readily amenable to genetic engineering and ex vivo
expansion, (c) iPSC-derived NK cells engineered to express a high-affinity, non-cleavable CD16a (hnCD16) and
membrane-bound IL-15/IL-15R without expression of CD38 enhances in vivo persistence and NK fitness and
permits use of anti-CD38 antibody for in vivo depletion of regulatory cells, (d) the construction of antibodies that
engage multiple targets, i.e. NK cells and tumor cells, with a stimulatory cytokine increase anti-tumor efficacy,
and, (e) large scale IEC manufacturing, providing 100s to 1000s of cell doses, is possible. These discoveries will
be further optimized and tested in relevant model systems in support of clinical translation. Project 1 will test
the hypothesis that engineered allogeneic CD4 Tregs can be engineered to express synthetic stimulatory
receptors and drug inducible CARs for maximum safety and reduced risk of exhaustion. Project 2 we will test
the hypothesis that off-the-shelf CD83 CAR iPSC CD8 iTregs can be engineered to avoid rejection and
exhaustion but retain potent tumoricidal activity against AML. And, Project 3 will test the hypothesis that the
combination of iNK genetic engineering and antigen specific targeting with TriKEs and CARs will enhance
specificity, potency, persistence for maximal AML killing.
Status | Active |
---|---|
Effective start/end date | 8/25/95 → 4/30/24 |
Funding
- National Cancer Institute: $2,072,348.00
- National Cancer Institute: $65,073.00
- National Cancer Institute: $1,940,892.00
- National Cancer Institute: $1,550,643.00
- National Cancer Institute: $2,065,942.00
- National Cancer Institute: $2,061,511.00
- National Cancer Institute: $1,275,301.00
- National Cancer Institute: $1,914,832.00
- National Cancer Institute: $2,042,270.00
- National Cancer Institute: $1,509,110.00
- National Cancer Institute: $2,148,642.00
- National Cancer Institute: $2,064,762.00
- National Cancer Institute: $1,914,865.00
- National Cancer Institute: $1,914,901.00
- National Cancer Institute: $2,101,526.00
- National Cancer Institute: $72,324.00
- National Cancer Institute: $1,260,346.00
- National Cancer Institute: $1,857,651.00
- National Cancer Institute: $1,466,762.00
- National Cancer Institute: $1,362,444.00
- National Cancer Institute: $2,228,606.00
- National Cancer Institute: $2,080,053.00
- National Cancer Institute: $2,157,390.00
- National Cancer Institute: $2,135,909.00
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Projects
- 27 Finished