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.
- QUAIL cannot grow extracellularly, which solves safety concerns from previous trials using LADD
- Listeria’s effect on the immune system can be harnessed for immunotherapy
- γδ T cells are exceptionally promising for immunotherapy
- Listeria potently and specifically activates γ9δ2 T cells for months and up to 1 year
- The γ9δ2 T cell subset is the preferred population for immunotherapy
- LADD-based strains, which serve as the foundation of QUAIL, profoundly activated and expanded γ9δ2 T cells in humans (CONFIDENTIAL, unpublished)
- 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
- Combining immune-activating microbes with TCEs in vivo results in greater T cell penetration into solid tumors and tumor clearance
Listeria
History and safety
Listeria has a long history in the clinic
LADD is the foundational strain for QUAIL
- Listeria-based therapeutics were generally well-tolerated in the clinic, but significant adverse events associated with extracellular growth were observed
- In clinical trials using LADD, there was one case of extracellular growth
QUAIL 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
- γδ T cell tumor infiltration is correlated with favorable outcomes, including in solid tumors
- γδ T cells can cross-present to ɑβ/CD8 T cells leading to robust and durable anti-tumor activity
- γδ T cell cytotoxicity is best characterized by their transcriptional profile
- γδ T cells cannot be studied in mice
γδ T cells are activated and expanded through pathogen-associated molecular pattern molecules (PAMPs) and damage-associated molecular patterns (DAMPs)
- PAMPs and DAMPs are the necessary “signal 0” for an effective immune response
- γδ T cells respond directly to PAMPs
In humans, γδ T cells have evolved to be exquisitely sensitive to Listeria
- Listeria’s effect on the immune system can be harnessed for immunotherapy
- Listeria is a potent activator of PAMP and DAMP signaling
- Listeria potently and specifically activates γ9δ2 T cells for months and up to 1 year
- 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
- Attenuated strains must be thoughtfully engineered to preserve immunogenicity
- Phosphoantigens (e.g., HMBPP) alone struggle to activate and expand γδ T cells
- 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 activated endogenously can can provide objective response in patients with non-Hodgkin lymphoma and MM
- Autologous γδ T cells activated ex vivo can be safely administered to patients with MM and penetrate into bone marrow
- γδ T cells from AML patient post-HSCT killed patient’s AML cells in vitro, were superior to NK cells at killing, and did not kill PHA-stimulated T blasts or B cells from same patient
γδ T cells that are activated and expanded by Listeria can improve outcomes for people with heme malignancies after receiving HSCT:
- Activating and expanding γδ T cells helps prevent infection and kill cancer cells in patients receiving ɑβ/CD8 T cell-depleted HSCT
- γδ T cells activated endogenously after auto hematopoietic stem cell therapy (HSCT) in patients with MM can target MM cells and support progression-free survival of 22.5 months (comparable to CAR-T); re-dosing zoledronate is ineffective
- 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
- Safety concerns limit the dose of CAR-T therapies that patients can tolerate. γδ T cells have not caused those toxicities and thus patients can benefit from much higher doses of γδ T cells
- Through multiple clinical studies, γδ T cells have not caused GvHD
- 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
- γδ T cells lytic capacity exceeds their capacity to produce cytokines, suggesting lower risk of CRS
- Step-fractionated dosing mitigates peak cytokine levels without compromising tumor response (mosunetuzumab, Blincyto)
- Affinity tuning can decrease off-target effects
- Increasing the number of tumor binding sites can increase the therapeutic index
γδ T cells in combination therapy
Pre-clinical models show the potential of pairing activated γδ T cells with biologics:
- Allogeneic γδ T cells expanded ex vivo with IL2 and BrHPP, then paired with monoclonal antibodies (e.g., Herceptin)
- Allogeneic γδ T cells expanded ex vivo with IL2 and zoledronate, then paired with CD3 bispecific (e.g., Blincyto)
- Allogeneic γδ T cells expanded ex vivo with IL2 and IL15 and zoledronate, then paired with γ9δ2-engaging bispecific