ApoptoSENS - Senolytic CAR-NK Cells

Apoptosens - Senolytic Car-nk Cells

VITACAR

Aging

Background Cellular senescence is the irreversible arrest of proliferation associated with a proinflammatory phenotype that can lead to tissue dysfunction and is implicated in numerous diseases. Natural Killer cells have an innate ability to remove senescent cells, however immune evasion can occur, which contributes to an accumulation of senescent cells with age. Several genetic and pharmacological studies have shown that elimination of senescent cells can ameliorate hallmarks of aging in both mice and humans, however more specific therapeutic interventions are required. ‍Aims, Hypothesis & Results ‍Dr. Amit Sharma is developing Chimeric Antigen Receptor Natural Killer (CAR-NK) cells to precisely and safely eliminate senescent cells in vivo. The team have identified a number of senescence-specific surface markers which could be targeted for senescence removal. They will focus on their most promising candidate senescent cell markers which will be more extensively validated using additional cell model paradigms (stressors), as well as in mouse models (cross-species validation). Validated surface markers will be used to generate monoclonal antibodies, which will then be confirmed for specificity against the target antigen. Appropriate CAR-NK cells will be created to further establish proof-of-concept for their approach of selective removal of senescent cells in their various model systems. Timeline The Sharma Lab will target the senescent cells they have identified by generating monoclonal antibodies against their senescence-specific surface markers. These monoclonal antibodies will then be used to create CAR-NK cells that can selectively eliminate senescent cells. Pre-clinical studies ‍Required Funding: $430,000 Duration: 24 Months VitaDAO Board Evaluation Writeup Dr. Amit Sharma has a strong scientific background in senescence and is based at the SENS Research Foundation, which provides strong support with a track record of successful spin-outs (e.g. Underdog Pharma 1). The removal of senescence cells is an attractive therapeutic approach to combat aging and promote longevity. Data from Dr. Sharma’s team and others showing NK cell cytotoxicity towards senescent cells provides proof-of-concept that using CAR-NK cells is a feasible strategy to eliminate senescent cells. The team’s identification of senescence-specific cell surface markers in vitro is extremely promising and if these markers are also expressed in senescent cells in vivo, this has the potential to be an effective senolytic therapy.

Description

‍Aims, Hypothesis & Results ‍Dr. Amit Sharma is developing Chimeric Antigen Receptor Natural Killer (CAR-NK) cells to precisely and safely eliminate senescent cells in vivo. The team have identified a number of senescence-specific surface markers which could be targeted for senescence removal. They will focus on their most promising candidate senescent cell markers which will be more extensively validated using additional cell model paradigms (stressors), as well as in mouse models (cross-species validation). Validated surface markers will be used to generate monoclonal antibodies, which will then be confirmed for specificity against the target antigen. Appropriate CAR-NK cells will be created to further establish proof-of-concept for their approach of selective removal of senescent cells in their various model systems.

Timeline The Sharma Lab will target the senescent cells they have identified by generating monoclonal antibodies against their senescence-specific surface markers. These monoclonal antibodies will then be used to create CAR-NK cells that can selectively eliminate senescent cells.

Pre-clinical studies ‍Required Funding: $430,000 Duration: 24 Months

VitaDAO Board Evaluation Writeup Dr. Amit Sharma has a strong scientific background in senescence and is based at the SENS Research Foundation, which provides strong support with a track record of successful spin-outs (e.g. Underdog Pharma 1). The removal of senescence cells is an attractive therapeutic approach to combat aging and promote longevity. Data from Dr. Sharma’s team and others showing NK cell cytotoxicity towards senescent cells provides proof-of-concept that using CAR-NK cells is a feasible strategy to eliminate senescent cells. The team’s identification of senescence-specific cell surface markers in vitro is extremely promising and if these markers are also expressed in senescent cells in vivo, this has the potential to be an effective senolytic therapy.

Team

Amit Sharma

Research Lead

Organisation

SENS Research Foundation

Experiment Cost

$253,000.00

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

TRL 3

TRL 4

Hypothesis formulated

Basic principles observed

Technology concept formulated

Experimental proof of concept

Technology validated in lab

Rationale

The project has conducted experimental laboratory work including surface marker discovery assays and preliminary CAR-mediated cytotoxicity testing in IMR-90 human fibroblasts, demonstrating 40-50% killing of senescent cells versus 10-25% killing of healthy cells. However, all experiments have been performed in basic 2D cell culture systems (IMR-90 fibroblast cell line) with artificially induced senescence, and no disease-relevant in vivo models, patient-derived organoids, or advanced disease-modeling systems have been utilized. Cross-species validation in mouse models is explicitly listed as planned future work.

Assessment

Low Confidence

RecommendationSUPPLEMENT

Total Score3.25

Overall Assessment

The ApoptoSENS project scores 3.25/5.0, indicating moderate-to-good early-stage potential at TRL 2. The strongest performance is in therapeutic relevance, with published proof-of-concept data identifying novel senescence markers and demonstrating selective killing in vitro. IP position is developing with antibody patents filed but CAR-NK patents pending. Key limitations include incomplete specificity (healthy cell killing observed), lack of in vivo validation, CAR-NK candidates not yet generated, and uncertainty about team's CAR-NK engineering experience. The project shows promise but requires significant de-risking through improved selectivity, in vivo validation, and candidate advancement to realize its therapeutic potential.

Weighted Score

Project Progress

All updates

All categories

Timeline

Project Score

Technology Readiness Level

PRE-TRL

TRL 1

TRL 2

TRL 3

TRL 4

Hypothesis formulated

Basic principles observed

Technology concept formulated

Experimental proof of concept

Technology validated in lab

Rationale

Assessment

Low Confidence

RecommendationSUPPLEMENT

Total Score3.25

Overall Assessment

Weighted Score

Therapeutic Relevance

Early experimental results support the hypothesis with in vitro data showing 40-50% senescent cell killing vs 10-25% healthy cell killing. Three novel surface markers (SENS-1, SENS-2, SENS-3) identified and validated across two senescence-induction methods (radiation, doxorubicin). Published peer-reviewed results reinforce biological relevance. Building on CAR-T precedent (Nature 2020 uPAR study). However, specificity gap between senescent and healthy cell killing is a concern, and only p16 used as senescence confirmation marker.

Therapeutic Optionality

Senescent cell accumulation is implicated in multiple aging-related conditions including fibrosis, tissue dysfunction, and chronic inflammation, suggesting moderate therapeutic optionality. CAR-NK platform could theoretically be applied to multiple senescence-driven indications. However, no specific alternative applications have been formally identified or explored yet, and the heterogeneity of beneficial vs harmful senescent cells limits broad application without further characterization.

Intellectual Property

Patents already filed for surface-marker antibodies and reagents for selective senescent cell targeting. CAR-NK method patent is planned but not yet filed. Reviewers noted likely Composition of Matter IP around CAR-NK sequences if successful. Novel targets (SENS-1, -2, -3) provide differentiation. However, no formal FTO assessment documented, and CAR-NK IP not yet formalized. Early results could strengthen filings, but IP status remains partially speculative.

Utility Of Candidates

Potential drug candidates are emerging in the form of monoclonal antibodies against SENS markers and planned CAR-NK cells, but neither has been fully generated yet. SENS-3 identified as most promising marker. In vitro proof-of-concept shows feasibility but CAR-NK generation is future work. Unclear if team has prior CAR-NK experience (feasibility risk). No lead candidate selected; antibody generation and CAR-NK construction are in proposal stage, not completed.

Prospects For Safety

CAR-NK cells offer safety advantages over CAR-T (lower cytokine storm risk, no need for immune suppression). However, preliminary data shows 10-25% killing of healthy cells, indicating off-target activity that represents a manageable but notable safety concern. Prior CAR-T uPAR studies showed toxicity at supratherapeutic doses (weight loss, hypothermia, proinflammatory cytokines). No formal toxicity studies conducted yet. Risk is identified and acknowledged but not yet characterized in vivo.