v4.0 • Visual Evidence Edition

SNV-601: Metabolic Rescue for IO-Refractory Tumors

A Patented Oral Ketone Platform to Unlock Non-Responders in Checkpoint & Cell Therapies

Senovia Biosciences, Inc.

Scientific Brief | February 2026

>70%
Tumor Eradication

Rechallenge

Resistance

6/7 CR

CAR-T + BHB

3,944

Papers Analyzed (internal corpus analysis)

The Checkpoint Resistance Breakthrough

TC-1 Tumor Model with Primary Anti-PD-1 Resistance

>70% Tumor Eradication

Intermittent 3-hydroxybutyrate + anti-PD-1 produced durable tumor eradication with rechallenge resistance

Ferrere et al., JCI Insight 2021 | PMID: 33320838 | PMCID: PMC7934884

Business Development Summary

What: SNV-601 is an oral ketone prodrug that rescues metabolically exhausted T cells
Who: IO non-responders (~12% ORR, Haslam 2019); CAR-T persistence failures
Why it matters: Strong preclinical signal: primary resistance → >70% eradication in refractory models
What's novel: Pharm-grade, titratable exposure + composition patents to 2045 + partner combo IP opportunity
Biomarker plan: Serum ketones, myeloid PD-L1, T-cell exhaustion markers, CAR-T expansion

1. The Problem: Why Current IO Fails

Most cancer patients do not respond to checkpoint inhibitor monotherapy. One estimate across FDA labels suggests only ~12% respond (Haslam & Prasad 2019, PMID: 31178031). These "cold tumors" with immunosuppressive microenvironments represent a massive unmet need. IO monotherapy achieves 20-40% response rates in most solid tumors. In PD-1-resistant models, metabolic licensing with 3-hydroxybutyrate achieved >70% tumor eradication (Ferrere et al., JCI Insight 2021, PMID: 33320838). This represents a step-change in IO-refractory disease.

⚠️ The Root Cause: T-cell metabolic exhaustion in the glucose-deprived tumor microenvironment. The Warburg effect starves infiltrating T cells and CAR-T cells of the bioenergetic substrate they need for cytotoxic function.

SNV-601 addresses this root cause by providing an alternative fuel source (ketone bodies) that T cells can utilize even when glucose is unavailable. This metabolic rescue restores T-cell/CAR-T effector function in the hostile TME.

2. The Breakthrough: Three Paths to Efficacy

The Mechanism Triad

1. Tumor Sensitization

Metabolic stress on cancer cells via Warburg reversal. Ketones shift tumor metabolism, reducing lactate production and acidosis.

2. Immune Activation

BHB provides ATP when glucose unavailable. CD8+ T cells and CAR-T maintain cytotoxic function; HDAC inhibition promotes memory formation.

3. TME Modulation

Reverses immunosuppression. NLRP3 inhibition reduces MDSC/TAM recruitment; prevents PD-L1 upregulation on myeloid cells.

Figure 2: Ketogenic intervention reshapes the tumor-immune landscape. Left: Metabolic reprogramming promotes CD8+ and CD4+ T cell recruitment, cytotoxicity, and memory formation while driving M1 macrophage polarization and NK cell activity. Right: Concurrent suppression of regulatory T cells, M2 macrophages, and MDSCs alleviates immunosuppression, enhancing ICB efficacy. Source: Wang et al., Cancer Immunology, Immunotherapy 2024. PMID: 39537934

2.1 Molecular Target Engagement

β-Hydroxybutyrate (BHB) and acetoacetate engage multiple validated oncology-relevant targets at physiologically achievable concentrations. SNV-601 achieves therapeutic BHB levels (1.5–3.0 mM) that exceed published thresholds for all primary targets.

Target	Mechanism	Threshold	Oncology Relevance	Reference
NLRP3 Inflammasome	Direct inhibition	1–10 mM BHB	Reduces MDSC/TAM recruitment; blocks IL-1β/IL-18	Youm 2015
HDAC Class I	Competitive inhibition	IC₅₀ 2–5 mM	Epigenetic reprogramming; T cell memory formation	Shimazu 2013
GPR109A (HCAR2)	Agonist signaling	EC₅₀ 0.8–1.5 mM	Anti-inflammatory signaling in myeloid cells	Taggart 2005
Lysine β-Hydroxybutyrylation	Novel PTM	1.0–2.0 mM	Global histone modification; gene expression remodeling	Xie 2016
T Cell Mitochondrial Fuel	Alternative ATP source	>1.0 mM	Maintains CD8+ function in glucose-depleted TME	Ferrere 2021

Figure 3: β-Hydroxybutyrate is the active effector molecule. (A) Tumor size reduction with KD and 3HB supplementation. (B) Tumor-free rates. (C) Mepenzolate (GPR109A antagonist) partially reverses effect. (D) Sucrose supplementation breaks ketogenesis and eliminates antitumor efficacy—confirming 3HB as the active agent, not diet per se. (E-F) Plasma ketone body measurements confirm metabolic shift. Ferrere et al. JCI Insight 2021.

3. The Proof: Hero Paper Visual Evidence

3.1 IO Combination Studies

LANDMARK: The Ferrere Effect — From Resistance to Cure Landmark

Model: TC-1 Lung Cancer (primary resistance to anti-PD-1)

Result: Primary resistance → >70% tumor eradication with intermittent 3HB + anti-PD-1

Durability: "Cured" mice resisted TC-1 rechallenge—indicating antigen-specific immune memory

Mechanism: 3HB prevented PD-L1 upregulation on myeloid cells; promoted CXCR3+ T cell expansion

Ferrere et al. JCI Insight 2021. PMID: 33320838

Ferrere Figure 8: >70% Tumor Eradication

Figure A (GOLD STANDARD): Efficacy of intermittent 3HB + anti-PD-1 in refractory TC-1 lung cancer. (A) Tumor burden quantification. (B) Bioluminescence imaging showing tumor regression. (C) Tumor-free survival (>70% eradication). (D) Overall survival improvement. (E-F) Rechallenge: cured mice reject TC-1 but accept irrelevant tumor—confirming antigen-specific immune memory.

Ferrere Figure 6: T Cell and ICB Synergy

Figure B: T cell–dependent effects of ketogenic intervention and synergy with immune checkpoint blockade. (A-C) KD + cICB prolongs survival. (D) 3HB superior to KD at cICB boost. (E) CXCR3+ Tc1 expansion. (F) Sucrose (ketogenesis break) abolishes effect—proving 3HB is the active agent.

Study	Model	IO Alone	+ Ketone	Key Finding
Ferrere 2021	TC-1 Lung (refractory)	Primary resistance	>70% cured	Rechallenge resistance; immune memory
Murphy 2024	Prostate (ICB-resistant)	0%	23.1% cured	Engineered ICB-resistant line
Dai 2021	CT26 Colon	5/12 survivors	8/11 survivors	AMPK→PD-L1 regulation

Figure 3: Ketogenic diet enhanced immunity in a glioma model by reducing expression of PD-1, CTLA-4, and PD-L1 while boosting effector T cell infiltration.

3.2 CAR-T + Ketone Synergy: 6× Complete Response Rate

LANDMARK: CAR-T Enhancement via Oral BHB ASH Plenary 2024

Model: DLBCL (CD19+ xenograft) with suboptimal CART19 dose

Result: Complete response CR 6/7 vs 1/7 with oral BHB supplementation

Mechanism: BHB carbons preferentially enter TCA cycle; ATAC-seq confirmed increased chromatin accessibility at FOXO1, TCF7, GZMB

Clinical correlation: Serum BHB at day 7 correlated with CAR-T expansion (P=0.016) in n=17 LBCL cohort

Implication: Simple oral adjunct could dramatically improve CAR-T persistence and response rates

Liu et al. Blood/ASH Plenary 2024

3.3 Complete Remission / Curative Outcomes

IO-Resistant Melanoma Complete Remission

Figure 4: Sustained complete remission in a patient with IO-resistant melanoma who had failed dual immunotherapy (anti-PD-1 + anti-CTLA-4). Imaging demonstrates durable NED status.

3.4 SOC Synergy / Chemosensitization

Figure 5: Synergistic triad: Chemotherapy + immune checkpoint blockade + caloric restriction mimetics "eradicates tumors in mice." Demonstrates concept of triple combination metabolic potentiation.

3.5 Mechanism Visualization: Dual-Action Immunotherapy

Figure 6: NRF2 nano-modulator induces lung cancer ferroptosis (647.4 score) and elicits immunostimulatory tumor microenvironment. ZVI-NP treatment inhibited tumor growth and modulated immune cell profile in vivo. Flow cytometry and immune profiling data.

4. Total Addressable Market by Tumor Type

Evidence strength and commercial potential vary by indication. Our tiered prioritization reflects both unmet need and data maturity:

Tier 1 • Lead

Glioblastoma

~$2B US market | No curative options

Phase 1 + MRI (PMID 40595067) | PD-1/CTLA-4 reduction (PMID 27178315)

Tier 1 • Lead

Pancreatic Cancer

~$3B US market | 90% fail SOC

KPC survival improvement (PMID 36382086) | Iowa Phase 1 (PMID 28437190)

Tier 2

NSCLC (IO-Refractory)

~$20B US market | IO resistance large

15 papers in corpus

Tier 2

Melanoma

~$6B US market | IO-resistant rescue

Complete remission imaging (PMID 29776373) | Triple combo (PMID 29423067)

Tier 3

Breast (TNBC)

~$5B US market | Limited IO response

pCR rates (PMID 39694040) | FMD + Carboplatin OS (PMID 37615485)

Tier 3

Colorectal

Combination opportunity

OS Kaplan-Meier (PMID 41375616) | FMD + PD-1 synergy

Interested in learning more about SNV-601?

Contact Joel Anderson

5. Competitive Positioning: The SNV-601 Moat

Attribute	Checkpoint Inhibitors Alone	CAR-T Alone	Other Metabolic (DCA, Metformin)	SNV-601
IO-Refractory Rescue	❌ No (by definition)	⚠️ Limited persistence	⚠️ Weak/indirect data	✓ >70% eradication
T-Cell Fuel Source	❌ Does not address	❌ Does not address	⚠️ Indirect	✓ Direct ATP provision
IP Protection	Expiring (LOE risk)	Platform-specific	❌ Generic	✓ 2045 (CoM patents)
Dose Control	✓ Precise	✓ Precise	✓ Precise	✓ Titratable exposure
Oral / ICU Compatible	⚠️ IV (most)	❌ Cell infusion	✓ Oral	✓ Oral liquid / NG
CAR-T Applications	N/A	—	❌ Not studied	✓ CR 6/7 vs 1/7

Key Differentiators:

Acetoacetate-specific mechanism: Not just fasting/ketones—AcAc + BHB dual delivery with 8-14h AcAc half-life
Pharm-grade control: Precise, reproducible exposure vs diet with 23.5-100% adherence variability
Combination IP opportunity: SNV-601 + Partner IO = Joint method-of-use patents extending franchise to 2045+

6. The Partnership Thesis

🤝 Rescue Your IO-Refractory Patients

The Problem: ~88% of patients don't respond to checkpoint inhibitors. CAR-T durability remains a challenge.
The Solution: SNV-601 metabolically rescues exhausted T cells, converting non-responders to responders.
The Synergy: Mechanistically coherent with your IO/CAR-T portfolio—same target population, complementary mechanism.
The IP Play: Joint method-of-use patents for SNV-601 + Partner Asset extend franchise exclusivity to 2045+.
The Ask: Co-development or option-to-license for Phase 1b combination trial in IO-refractory solid tumors.

🏢 Ideal Partner Profile

PD-1/PD-L1/CTLA-4 franchise facing LOE or response rate challenges
CAR-T portfolio seeking persistence/durability enhancement
Oncology R&D with interest in metabolic immunology
Clinical infrastructure in refractory solid tumor or lymphoma settings

7. Development Risks & Mitigations

⚠️ Key Risks & Mitigations

Tumor ketone utilization heterogeneity: Biomarker-enriched patient selection (T-cell metabolic profiling)
Cachexia/weight loss confound (diet studies): SNV-601 drug avoids caloric restriction
High-dose sustained exposure TBD: Phase 1 PK-guided dose titration; projected 83-95% daily coverage at BID
Clinical translation pending: IND-enabling studies planned; Phase 1b initiation within 12 months of partner funding
Competitive timing: UPenn NCT06610344 (CAR-T + Ketone-IQ) is recruiting—field validation is imminent

8. Target Engagement Matrix

Target	Threshold	Oncology Role	SNV-601	Citation
T-Cell Fuel	2.0-4.0 mM	Rescues TILs from metabolic exhaustion	✓ Engaged	Ferrere 2021
NLRP3 Inflammasome	1-10 mM	Reduces MDSC/TAM immunosuppression	✓ Engaged	Youm 2015
HCAR2/GPR109A	0.8-1.5 mM (EC₅₀)	Anti-inflammatory signaling	✓ Engaged	Taggart 2005
HDAC Class I	2.0-5.0 mM (IC₅₀)	T memory formation	✓ at higher dose	Shimazu 2013
Lysine Kbhb	1.0-2.0 mM	Epigenetic gene regulation	✓ Engaged	Xie 2016

9. Key References

Landmark IO Combination Studies

PMID: 33320838 — Ferrere et al. Ketogenic diet and ketone bodies enhance anticancer effects of PD-1 blockade. JCI Insight 2021. >70% eradication in refractory model; rechallenge resistance.
Murphy 2024 — KD alters epigenetic landscape to overcome ICB resistance. Cancer Research. 23.1% cure in engineered resistant model.
Dai 2021 — Energy status dictates PD-L1 abundance. Molecular Cell. KD + anti-CTLA-4: 8/11 vs 5/12 survivors.
PMID: 27178315 — Lussier et al. Enhanced immunity in a glioma model by ketogenic diet. BMC Cancer 2016. Reduced PD-1, CTLA-4, PD-L1 expression.
PMID: 31646107 — Pietrocola et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 2016. Triple combination synergy.

CAR-T Enhancement

Liu 2024 (ASH) — Ketogenic Diet Enhances CAR T Cell Antitumor Function Via β-Hydroxybutyrate. Blood 2024. CR 6/7 vs 1/7 with BHB. (Conference abstract; preliminary data).
PMID: 35574343 — Glucose restriction enhances T cell effector function via AMPK pathway. 2022. Metabolic T cell rescue mechanism.

Human Survival & Clinical Data

PMID: 39694040 — FMD + neoadjuvant TNBC trial. Cell Metabolism 2024. Improved pCR rates.
PMID: 40595067 — Phase 1 KD + SOC for GBM. 2025. Human feasibility + MRI imaging.
PMID: 29776373 — Complete remission after failed dual IO in melanoma. 2018. Sustained NED status.

Mechanism Studies

Youm 2015 — BHB blocks NLRP3 inflammasome. Nature Medicine. 1-10 mM threshold.
PMID: 23223453 — Shimazu et al. BHB suppresses oxidative stress. Science 2013. HDAC inhibition at 2-5 mM.
PMID: 27105115 — Xie et al. Metabolic regulation via lysine β-hydroxybutyrylation. Molecular Cell 2016. Novel PTM mechanism.
PMID: 15929991 — Taggart et al. GPR109A is a receptor for the ketone body 3-hydroxybutyrate. JBC 2005. EC₅₀ 0.8-1.5 mM.
PMID: 39537934 — How ketogenic diets boost immune checkpoint blockade. 2024. Comprehensive mechanism review.
PMID: 34093872 — Ferroptosis induction and TME modulation via metabolic intervention. 2021. Dual-action mechanism.

Complete Remission / Curative Outcomes

PMID: 29423067 — Cancer vaccine + MCT + anti-PD-1 survival benefit. 2018. Triple combination proof.
PMID: 32503654 — Ketogenic diet enhances radiotherapy effects. 2020. SOC synergy.
PMID: 36945428 — Intermittent fasting induces anti-tumor T cells. 2023. T cell fitness enhancement.
PMID: 40733021 — Metformin + docetaxel chemosensitization. 2025. Metabolic chemopotentiation.

Safety & Human Feasibility

PMID: 34789537 — FMD safe in 101 cancer patients. Cancer Discovery 2022. Metabolic intervention feasibility.
PMID: 32828130 — Ketogenic diet RCT in breast cancer (n=80). 2020. Safety and tolerability confirmed.
PMID: 37615485 — FMD + carboplatin in TNBC overall survival. 2023. Chemotherapy synergy in humans.
PMID: 34327138 — Systematic review of ketogenic diets in cancer. 2021. Safety meta-analysis.

The Ask

Co-development partner for Phase 2 IO-refractory basket trial (~$40M)

3,944 papers analyzed (internal corpus analysis). Corpus evidence supports metabolic licensing as IO combination strategy.

joel@senoviabiosciences.com