Breakthrough Clinical Results
LIfT BioSciences announced the presentation of preclinical data on its first-in-class Immunomodulatory Alpha Neutrophils (IMANs) at the ISCT 2025 Annual Meeting. The data highlighted IMANs' dual mechanism of action: direct tumor cytotoxicity and potent immunomodulatory effects. IMANs demonstrated superior tumor penetration and killing capabilities across multiple solid tumor types, effectively converting 'cold' tumors into immune-responsive 'hot' tumors. This dual action rejuvenates the innate immune system and drives a durable immune response, offering a potential new approach for treating solid tumors where current therapies fall short. The company is preparing to advance IMANs toward clinical trials.
Key Highlights
- IMANs demonstrate superior tumor penetration and direct cancer cell killing across multiple solid tumor types.
- IMANs possess a dual mechanism of action, converting 'cold' tumors into 'hot' tumors and activating systemic anti-cancer immunity.
- Preclinical data showed persistent tumor infiltration and NK cell recruitment for over 21 days in humanized models.
- LIfT BioSciences is preparing to advance IMANs toward clinical trials.
Emerging Mechanism of Action
CAR T-cell therapy has shown remarkable success in treating hematological malignancies, but its efficacy in solid tumors has been limited. Several key mechanisms of action (MoAs) and strategies are emerging to address these limitations:
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Targeting the tumor microenvironment (TME): The TME of solid tumors is often immunosuppressive, hindering CAR T-cell function. Strategies to overcome this include:
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Engineering CAR T-cells to secrete cytokines: This can help to counteract the immunosuppressive factors in the TME and enhance T-cell activity.
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Combining CAR T-cell therapy with checkpoint inhibitors: This can further enhance T-cell activity by blocking inhibitory signals.
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Targeting other immune cells in the TME: For example, CAR macrophages (CAR-Ms) are being investigated for their ability to infiltrate tumors and enhance anti-tumor immunity.
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Improving tumor infiltration and trafficking: CAR T-cells often struggle to reach and penetrate solid tumors. Strategies to improve this include:
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Regional delivery of CAR T-cells: Injecting CAR T-cells directly into the tumor site can improve their infiltration and efficacy.
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Engineering CAR T-cells to express chemokine receptors: This can help to attract CAR T-cells to the tumor site.
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Addressing tumor heterogeneity and antigen escape: Solid tumors are often heterogeneous, with different cells expressing different levels of target antigens. This can lead to antigen escape, where tumor cells stop expressing the target antigen and become resistant to CAR T-cell therapy. Strategies to address this include:
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Targeting multiple tumor antigens: This can help to prevent antigen escape by targeting multiple antigens on the tumor cells.
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Engineering CAR T-cells to target intracellular antigens: This can help to target tumor cells that have downregulated surface antigens.
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Enhancing CAR T-cell persistence and function: CAR T-cells often have a limited lifespan and can become exhausted in the TME. Strategies to enhance their persistence and function include:
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Engineering CAR T-cells with improved costimulatory domains: This can help to enhance T-cell activation and proliferation.
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Combining CAR T-cell therapy with targeted inhibitors: This can help to enhance CAR T-cell infiltration, tumor recognition, and cytotoxicity, while also reducing exhaustion and toxicity.
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Other emerging CAR cell therapies:
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CAR-NK cells: These cells do not require HLA matching and have limited toxicity, making them a promising alternative to CAR T-cells.
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CAR-iNKT cells: These cells have both innate and adaptive immune properties, making them a promising candidate for targeting solid tumors.
In addition to CAR T-cell therapy, other MoAs are being investigated for solid tumors, including:
- T-cell engagers (TCEs): These molecules can connect a patient's cytotoxic T cells with cancer cells, leading to potent redirected lysis. TCEs targeting peptide-MHC complexes are expanding the target space for solid tumor therapy to intracellular targets.
- Antibody-drug conjugates (ADCs): These molecules combine the selectivity of monoclonal antibodies with the cell-killing properties of chemotherapy. ADCs are being investigated in combination with other anticancer drugs, including chemotherapy, molecularly targeted agents, and immunotherapy.
- Oncolytic viruses (OVs): These viruses selectively infect and kill tumor cells while sparing normal cells. OVs are being investigated in combination with immunotherapy, such as immune checkpoint blockade and CAR T-cells.
- PROteolysis Targeting Chimera (PROTAC) technology: This technology utilizes an event-driven MoA to degrade target proteins, offering advantages over traditional occupancy-driven small molecule inhibitors.
Overall, the field of solid tumor therapy is rapidly evolving, with multiple promising MoAs and strategies emerging. Further research is needed to optimize these approaches and translate them into effective clinical therapies.
Drug used in other indications
Immunomodulatory alpha neutrophils (IMANs) are not explicitly mentioned in the provided text. However, the provided research papers discuss various immunomodulatory agents and their applications in different diseases, including those affecting neutrophils. While solid tumors are a significant area of research for immunomodulatory therapies, other indications are also being explored. Based on the provided text, these include:
- Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): A neurological disorder characterized by progressive or relapsing weakness and numbness. Trials have investigated azathioprine, interferon beta-1a, and methotrexate, but with limited success. One trial of azathioprine (27 participants) showed no significant benefit. Two trials of IFN beta-1a (77 participants total) showed no significant benefit. One methotrexate trial (60 participants) showed no significant benefit.
- Infectious diseases: Immunomodulatory therapies are being explored as alternatives or adjuncts to antibiotics, especially with rising antibiotic resistance. Specific agents and trials are not detailed in this context within the provided text, but the concept is mentioned as an area of active research.
- Inflammatory diseases: Conditions like osteoarthritis and rheumatoid arthritis are being targeted with immunomodulatory agents like APPA (a combination of apocynin and paeonol). APPA has shown promise in preclinical studies by inhibiting neutrophil degranulation and cytokine signaling.
- Autoimmune diseases: A broad category including conditions like rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Various agents are being investigated, including TNF-α inhibitors, TL1A (Tumor necrosis factor-like cytokine 1A) inhibitors, and others. Specific trials and agents vary depending on the specific autoimmune disease.
- Neuroimmunological and neurodegenerative diseases: Conditions like multiple sclerosis and amyotrophic lateral sclerosis are being explored as potential targets for immunomodulatory antibiotics like tetracyclines and cephalosporins. Specific trials are not detailed in the provided text.
- Sepsis: CAAP48, a C-terminal alpha-1 antitrypsin fragment, has been identified as a potential sepsis biomarker with immunomodulatory functions, particularly on neutrophils. Its diagnostic and therapeutic potential is being investigated.
- Hematological malignancies: Immunomodulatory imide drugs (IMiDs) like lenalidomide and pomalidomide are used in combination with targeted immunotherapies. Their mechanisms of action and efficacy in enhancing antitumor T cell and NK cell responses are being studied.
Intervention models for these trials vary depending on the specific disease and agent being investigated. Common models include:
- Randomized controlled trials (RCTs): The gold standard for evaluating treatment efficacy. Participants are randomly assigned to either a treatment group or a control group (placebo or standard treatment). Examples include the trials of azathioprine, interferon beta-1a, and methotrexate in CIDP.
- Preclinical studies: Laboratory and animal studies conducted before human trials to evaluate safety and efficacy. An example is the research on APPA for osteoarthritis and rheumatoid arthritis.
- Observational studies: Studies where researchers observe participants without intervening. These can provide valuable information about disease progression and potential risk factors, but they cannot establish cause-and-effect relationships. Observational studies are mentioned as providing insufficient evidence for the efficacy of certain immunomodulatory agents in CIDP.
- Pilot studies: Small-scale studies conducted to assess the feasibility and safety of a new treatment before larger trials are launched. An example is the open-label pilot study of infliximab in SpA.
- In vitro studies: Experiments conducted in controlled laboratory settings using cells or tissues. These can provide valuable insights into the mechanisms of action of immunomodulatory agents, as seen in studies of caffeine's effects on immune cells.
- In vivo studies: Experiments conducted in living organisms, typically animals. These can provide information about the efficacy and safety of a treatment in a more complex biological system, as seen in studies of hypertonic saline resuscitation in trauma.
It is important to note that the specific intervention models used vary depending on the research question being addressed and the stage of drug development. For example, early-stage research often relies on in vitro and in vivo studies, while later-stage research typically involves RCTs.
This information is based on the provided text and may not represent the full spectrum of ongoing research on immunomodulatory therapies.
Company Mechanism of Action
The provided text does not contain information about the specific mechanisms of action used by drugs from LIfT BioSciences. Therefore, I cannot answer your question using the provided context.
It's important to note that accessing external websites or specific files online is beyond my capabilities as a large language model.