Locoregional and systemic immunomodulation with intratumoral TCR agonism
Author(s)
Mcclain, Claire Alexandra
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Abstract
Cancer immunotherapies have revolutionized cancer treatment however, success in solid
tumors remains limited. With many solid tumors exhibiting heterogeneity and rapid
growth, developing an easily accessible, off the shelf, potent T cell modulator that
leverages the immune system’s intrinsic anti-tumor mechanisms to quickly to combat
tumor progression is advantageous. Here we demonstrate a single dose of aCD3 induces
potent tumor control in a B16F10 orthotopic tumor model and is well tolerated. Not only
does this antigen agnostic TCR agonism strategy result in mobilization of therapeutic T
cell populations into the circulation and increase tumor infiltration of effector CD8 T cell
subsets, but it also synergizes with current cancer immunotherapies, namely immune
checkpoint blockade (ICB) aPD-1 improving overall survival. Further, therapy was not
restricted to an intratumoral route of administration, where tumor draining lymph node
(TDLN) directed administration resulted in the expansion of effector CD8 T cells in the
circulation and subsequent tumor infiltration. This minimally invasive therapeutic strategy
induces remodeling of CD8 T cell subsets in both the TDLN and NDLN indicating both
local and systemic immune modulation. The quality of CD8 T cell subset mobilized into
the circulation has strong implications on the efficacy of current cancer immunotherapies,
therefore understanding the flux of key immune population from lymphoid tissues through
the circulation into the tumor is essential in improving cancer immunotherapies.
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Date
2024-12-02
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Resource Type
Text
Resource Subtype
Dissertation (PhD)