Our Science

DC Hyperactivation: A New Immunotherapy Paradigm

We are working towards Generating Immunity for Life by inducing exceptionally durable memory T cells via Corner’s proprietary hyperactivators. Our hyperactivators increase the intelligence of dendritic cells, the master regulators of T cells. Our platform represents a new class of multi-purpose immunotherapies that target the central actions of our immune system to treat a broad range of cancer and infectious diseases.

Why are we unique?

We generate exceptional memory T cells that provide life-long immunity

Our platform uses hyperactivators, a new class of immunotherapy. Hyperactivators enhance the intelligence of dendritic cells (DCs) to generate T cell mediated immunity—for life. As apex regulators of our immune system, hyperactive DCs induce a diverse repertoire of long-lived memory T cells beyond what is possible with current therapies.

We unleash the power of inflammasome activation within live DCs

Our hyperactivators activate inflammasomes within living DCs to produce IL-1β, the key T cell memory signal. Prior therapies targeting DCs have failed to provide durable immunity. They either cannot stimulate the IL-1β signal, or they use inflammasome stimuli that kill DCs via pyroptosis. We are shifting this paradigm by unleashing IL-1β signals from living DCs.

We lead DCs to be in the right place, at the right time

Our hyperactivators are uniquely capable of stimulating DC migration to lymph nodes, where naïve and memory T cells are activated. While previous attempts to stimulate DC activities were poor inducers of migration, we ensure these apex immune regulators are in the right place and at the right time, to promote durable immunity.

We are antigen agnostic

Our multi-purpose platform can target a wide array of antigens ranging from known single antigens to a complex source of unidentified antigens. We are leading a new era of rapid and low-cost immunotherapies. We provide personalized immunotherapies to be available for patients within days.

Dendritic Cells and Immunotherapies

Dendritic Cell Hyperactivation

An ideal immunotherapy induces robust and durable T cells that treat the disease and protects the patient from the disease recurrence for life.

DCs that receive infection-like signals become active and upregulate 3 functions that are necessary for their interaction with T cells:
  1. Antigen presentation
  2. Co-stimulatory molecule expression
  3. Secretion of cytokines that activate T cells

However, these 3 signals are not sufficient to promote long-lived memory T cells.

An ideal immunotherapy induces robust and durable T cells that treat the disease and protects the patient from the disease from recurring for life.

DCs that receive an injury-like signal in addition to the infection-like signal become hyperactive1,2.
Corner Therapeutics proprietary hyperactivating molecules add two critical functions to DCs.

  1. Migration in high numbers to lymph nodes where they can interact with naïve and memory T cells3.
  2. Production of T cell memory cytokine IL-1β from viable DCs, by unleashing their inflammasome machinery.
These 5 signals are critical to promote long-lived memory T cells3,4.
IL-1β is critical in generating new long-lived memory T cells as well as reactivating existing memory T cells5,6. Corner’s ability to promote IL-1β release from viable hyperactive DCs allows the rapid expansion of existing memory T cells and the differentiation of new antigen-specific T cells that combat disease throughout the life of the patient5-9.

Bridging knowledge gaps that limit the success of current immunotherapies

Antigen uptake and presentation

DCs ingest antigens from the body’s tissues and present them on their surface to T cells and other lymphocytes to initiate an immune response. Without antigen presentation, an adaptive immune response – robust and specific to a piece of a pathogen or tumor – cannot be triggered.

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Co-stimulation


DCs provide co-stimulatory signals to T cells and other lymphocytes when they detect pathogens in their environment to enable an effective inflammatory immune response. In the absence of co-stimulation, T cells and other lymphocytes that interact with DCs become anergic – they do not proliferate or develop their effector functions.

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Short lived effector T cells


Short-lived effector T cells produce effector cytokines to fight active infections or tumors, but they are transient. Since their numbers wane after few weeks, these cells are not ideal to fight recurring diseases or tumors.

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Polarization cytokines


DCs that detect pathogens or damage signals make cytokines that direct the differentiation of T cells and impact T cell longevity. Without these cytokines, T cells may develop into subtypes that less effectively combat pathogens or tumors.

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Migration


DCs must move to lymph nodes that drain the infected tissue or cancer to initiate an adaptive immune response. Lymph nodes contain abundant pools of naïve T cells and are the primary sites of DC-T cell interactions that enable adaptive immune responses. In the absence of DC migration, DCs are unable to interact with T cells.

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IL-1β secretion

DCs can provide memory-inducing cytokines, such as IL-1β, to both generate new (de novo) memory T cells and reactivate existing memory T cells. Hyperactive DCs continuously secrete IL-1β while remaining viable in proximity to T cells. Without the IL-1β signal, a poor memory response is achieved, and patients do not gain lifelong protective immunity.

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Long-lived memory T cells


Long-lived memory T cells have a long-life span and act as persistent reservoirs of immunity that can be reactivated by subsequent antigen encounters. These cells are ideal to fight hard-to-treat infections and cancer, as they can provide long-term protection from re-infection and tumor recurrence.

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Lifelong protective immunity


DCs must perform all five functions to maximally drive long-lived memory T cells. Without all 5 characteristics: antigen presentation, co-stimulatory molecule expression, secretion of polarization cytokines, enhanced migration, and IL-1 β secretion, DCs will not generate protective immunity for life.

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References

  1. Zanoni, I. et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science (1979) 352, 1232–1236 (2016).
  2. Zhivaki, D. & Kagan, J. C. Innate immune detection of lipid oxidation as a threat assessment strategy. Nature Reviews Immunology Preprint at https://doi.org/10.1038/s41577-021-00618-8 (2021).
  3. Zhivaki, D. et al. Inflammasomes within Hyperactive Murine Dendritic Cells Stimulate Long-Lived T Cell-Mediated Anti-tumor Immunity. CellReports 33, 108381 (2020).
  4. Zhivaki, D. & Kagan, J. C. NLRP3 inflammasomes that induce antitumor immunity. Trends Immunol (2021) doi:10.1016/j.it.2021.05.001.L
  5. Ben-Sasson, S. Z. et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J Exp Med 210, 491–502 (2013).
  6. Lee, P.-H. et al. Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells. J Exp Med jem.20181218 (2019) doi:10.1084/jem.20181218.
  7. Ben-Sasson, S. Z., Wang, K., Cohen, J. & Paul, W. E. IL-1 Strikingly Enhances Antigen-Driven CD4 and CD8 T-Cell Responses. Cold Spring Harb Symp Quant Biol 78, 117–124 (2013).
  8. Ben-Sasson, S. Z. et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc Natl Acad Sci U S A 106, 7119–24 (2009).
  9. Jain, A., Song, R., Wakeland, E. K. & Pasare, C. T cell-intrinsic IL-1R signaling licenses effector cytokine production by memory CD4 T cells. Nat Commun 9, 1–13 (2018).
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