Laguna Bio
LAGUNA BIO
SUPERCHARGING IMMUNOTHERAPY
This guide highlights the scientific background behind Laguna's therapeutic approach. Each statement links to a publication that you can access and download. If you only have time for a few papers, we think you’ll find these first few especially helpful. For additional information, please continue on.
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Listeria’s effect on the immune system can be harnessed for immunotherapy
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Bispecific T cell engagers (BiTEs) direct γδ T cells against tumors
Listeria
History and safety
Listeria has a long history in the clinic
LADD is the foundational strain for Laguna Listeria
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In clinical trials using LADD, there was one case of listeriosis
Laguna Listeria cannot grow extracellularly, which solves safety concerns from previous trials using LADD
Activation and expansion of γδ T cells
γδ T cells are exceptionally promising for immunotherapy
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γδ T cell tumor infiltration is correlated with favorable outcomes, including in solid tumors
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γδ T cells can cross-present to ɑβ/CD8 T cells leading to robust and durable anti-tumor activity
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γδ T cell cytotoxicity is best characterized by their transcriptional profile
γδ T cells are activated and expanded through pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs)
In humans, γδ T cells have evolved to be exquisitely sensitive to Listeria
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Listeria’s effect on the immune system can be harnessed for immunotherapy
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Listeria activates and expands γδ T cells through mechanisms other than HMBPP, likely PAMPs and DAMPs - No existing small molecule or antibody-based activation of γδ T cells can stimulate multiple paths of activation like Listeria
Other approaches are poor γ9δ2 T cell activators
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Dead Listeria are poor immune activators, necessitating live attenuated strains
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Phosphoantigens (e.g., HMBPP) alone struggle to activate and expand γδ T cells
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Repeated phosphoantigen administration can impair γδ T cells - However, repeated administration of Listeria leads to continuous activation and expansion of γδ T cells in our results from a human study
Other immune cell populations have limitations for immunotherapy
Potential with other immune cells
MAIT cells are another promising immune population for immunotherapy
Biologics: mAbs and bispecifics / BiTEs
Several companies are developing γ9δ2-engaging bispecifics
Cytokine release syndrome (CRS) is a concern with biologics, but can be managed through several strategies
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Step-fractionated dosing mitigates peak cytokine levels without compromising tumor response (mosunetuzumab, Blincyto)
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Increasing the number of tumor binding sites can increase the therapeutic index
Graft versus host disease (GvHD) is a concern with traditional ɑβ CAR-T therapy, but is not a concern with γδ T cells
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CAR-T therapy dosing of ~10^8 balances safety and efficacy considerations
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Traditional CAR-T is limited by GvHD, but γδ T cells don’t cause GvHD
Activation + biologics combination therapy
Pre-clinical models show the potential of pairing activated γ9δ2 T cells and MAIT cells with biologics:
Activation as a monotherapy
γδ T cells that are activated and expanded by Listeria can improve outcomes for people with heme malignancies after receiving hematopoietic stem cell therapy (HSCT):
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For pediatric patients receiving T cell-depleted haplo-HSCT in combination with zoledronate to activate endogenous γδ T cells:
