Laguna Bio
Literature Review
We’ve put together this guide that highlights the scientific background behind our 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 especially helpful. For additional information, please continue on.
γδ T cells penetrate into the bone marrow of multiple myeloma patients, and improve objective responses in patients with heme malignancies including NHL and multiple myeloma, and after hematopoietic stem cell therapy (HSCT)
γδ T cell cytotoxicity can enhance the tumor killing of monoclonal antibodies including alemtuzumab (CLL), rituximab (NHL, CLL), and trastuzumab (breast, stomach)
Bispecific T cell engagers (TCEs) can direct γδ T cells to kill cancer cells through CD3 and γδ-specific TCRs
Listeria
History And Safety
In clinical trials using LADD, there was one case of extracellular growth
Activation and expansion of γδ T cells
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
This potent and specific activation is conserved with LADD-based strains, which serve as the foundation of QUAIL: LADD-based strains profoundly activated and expanded γ9δ2 T cells in humans (CONFIDENTIAL, unpublished)
Listeria also 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 γδ T cell activators
Dead or fixed Listeria are poor immune activators, necessitating live attenuated strains
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
Anti-tumor efficacy of γδ T cells
γδ T cells as monotherapy
γδ T cells that are activated and expanded by Listeria can improve outcomes for people with heme malignancies such as multiple myeloma (MM) and acute myeloid leukemia (AML):
γδ T cells that are activated and expanded by Listeria can improve outcomes for people with heme malignancies after receiving HSCT:
For pediatric patients receiving T cell-depleted haplo-HSCT in combination with zoledronate to activate endogenous γδ T cells:
Across multiple clinical studies, expanding and activating γδ T cells has been observed to be very safe, well-tolerated, and did not cause common toxicities such as cytokine release syndrome (CRS) or graft vs. host disease (GvHD) that are regularly observed in other immunotherapy approaches
LADD expansion of γ9δ2 T cells achieves at least 109 γδ T cells in the peripheral blood, which is 10x more than Toxicity-limited CAR-T dosing
Biologics: mAbs and TCEs
Several companies are developing γδ-engaging TCEs
CRS is a concern with immunotherapies, but can be managed through several strategies
Step-fractionated dosing mitigates peak cytokine levels without compromising tumor response (mosunetuzumab, Blincyto)
γδ T cells in combination therapy
Pre-clinical models show the potential of pairing activated γδ T cells with biologics:
