Confronting NSCLC’s Hypoxia and Acidosis-Driven Barriers to Therapy

Non-small cell lung cancer (NSCLC) accounts for four out of every five cases of lung cancer and remains the leading cause of cancer-related death worldwide(1). Over the past decade, targeted therapies and immunotherapies have reshaped standards of care and extended survival. Yet a stubborn reality persists: between 70–85% of patients experience resistance to immunotherapy, whether primary or acquired.

Part of the explanation lies not in tumor genetics, but in the tumor microenvironment (TME). Two defining features, oxygen deprivation (hypoxia) and extracellular acidity (low pH), are now recognized as central drivers of both tumor survival and therapy resistance(2). In effect, cancer doesn’t just grow; it engineers a protective niche that blunts treatment and dampens the immune system(3).

Why Hypoxia and Acidosis Matter in NSCLC3

Within NSCLC tumors, blood flow is patchy, leaving regions poorly perfused and chronically deprived of oxygen. Under these conditions, cells activate hypoxia-inducible factor 1α (HIF-1α), a master switch that rewires metabolism toward glycolysis and lactate release. The result is a profoundly acidic microenvironment, with pH values sometimes dipping to 6.5 or lower.

This state actively promotes disease progression:

  1. New blood vessel growth (angiogenesis): Hypoxia increases VEGF secretion, fueling abnormal blood vessel growth.
  2. Spread and invasion: Hypoxia triggers epithelial-to-mesenchymal transition (EMT), enabling migration and metastasis.
  3. Immune suppression: Acidic conditions impair T cell, Natural Killer (NK) cell, and dendritic cell activity, undermining the very immune functions that checkpoint inhibitors and other immunotherapies rely on to eliminate tumors.
  4. Therapy resistance: Acidic pH reduces chemotherapy uptake, especially weak bases, and dampens drug efficacy.

Hypoxia and acidosis are therefore not byproducts but partners in crime that help tumors resist and survive.

The Hidden Force Behind Drug Resistance4

Resistance is often viewed as a genetic issue, driven by mutations in key oncogenes such as EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), or KRAS (Kirsten rat sarcoma viral oncogene), that allow tumor cells to bypass or outsmart targeted therapies. But even without such mutations, a hostile TME can undermine treatment. Under acidic conditions, cancer cells reduce drug uptake, reprogram survival pathways, and increase the activity of efflux pumps (specialized transport proteins that actively expel drugs from the cell, preventing them from reaching their targets).

Immunotherapies are equally vulnerable. Checkpoint inhibitors like anti–PD-1 depend on active cytotoxic T cells to recognize and destroy tumor cells. In acidic conditions, however, these T cells lose their effectiveness: interferon-γ secretion decreases, weakening their ability to signal and recruit other immune cells; cytotoxic activity diminishes, reducing direct tumor killing; and populations of myeloid-derived suppressor cells (MDSCs) expand, further silencing the immune response. Together, these changes turn the tumor into an immunologically “cold” environment, one that resists checkpoint blockade and remains effectively invisible to the immune system.

How Hypoxia and Acidosis Enable Immune Escape and Spread3

Low oxygen and low pH reshape both the immune landscape and the physical structure of the tumor. Acidosis impairs antigen presentation, reducing the immune system’s ability to recognize tumor cells; it also drives PD-L1 upregulation, allowing cancer cells to directly suppress T cell activity, and skews dendritic cells toward tolerance rather than immune activation. At the same time, hypoxia remodels the extracellular matrix, loosening structural barriers and clearing pathways that facilitate invasion and metastasis. Together, these forces create a dual advantage for the tumor: they shield it from immune attack while enabling it to spread to new sites.

Strategies to Break the Barrier5,6

To address these challenges, researchers are developing therapies that reprogram the TME:

  1. Hypoxia-inducible factor (HIF) inhibitors: Drugs that block HIF transcription factors, the “switches” tumors use to adapt to low oxygen by driving angiogenesis, metabolic reprogramming, and survival.
  2. Monocarboxylate transporter (MCT) blockers: Inhibitors of membrane transport proteins that shuttle lactate and protons out of cancer cells; by blocking them, acid buildup and lactate-driven signaling can be reduced.
  3. Carbonic anhydrase IX (CAIX) inhibitors: Agents that target CAIX, an enzyme induced under hypoxia that helps tumors regulate pH and survive in acidic environments.
  4. Systemic buffers: Agents such as sodium bicarbonate that raise blood and tissue pH more generally, but with limited specificity for tumors and potential systemic side effects. By contrast, one approach stands out: L-DOS47, a targeted pharmacological therapy designed specifically to normalize tumor acidity within the tumor microenvironment, offering greater precision and therapeutic potential.

L-DOS47: A Targeted pH Normalizer7

L-DOS47 is a first-in-class antibody-enzyme conjugate (AEC) that delivers a highly localized correction of tumor acidity. It integrates a camelid-derived single-domain antibody (nanobody) targeting CEACAM6 (an adhesion molecule minimally expressed in healthy tissues but overexpressed in many solid tumors, including NSCLC) with a urease enzyme. Once bound to CEACAM6-expressing tumor cells, the urease component becomes catalytically active and converts naturally occurring urea into ammonia and bicarbonate, raising local pH and counteracting acidity.

This localized alkalization leads to:

  • Immune reactivation: T cells and NK cells perform better in physiological pH, making L-DOS47 a potential amplifier of PD-1/PD-L1 checkpoint inhibitors.
  • Improved drug penetration: Acidity no longer traps weak-base chemotherapy drugs outside tumor cells, improving their uptake.
  • Specific targeting: By binding CEACAM6, activity is focused where it’s needed, in tumor tissues, avoiding non-specific systemic alkalization.

Preclinical and clinical evidence is encouraging. In mouse models of pancreatic adenocarcinoma, combining L-DOS47 with the anti-PD-1 antibody pembrolizumab achieved a 70% greater reduction in tumor volume and a 50% greater reduction in tumor weight compared to pembrolizumab alone, within 28 days.(source) Earlier clinical studies in Stage IV NSCLC showed that L-DOS47 combined with pemetrexed and carboplatin improved responses in heavily pre-treated patients, supporting the rationale that normalizing tumor pH can enhance the activity of ionizable, weak-base chemotherapies, such as pemetrexed, and suggesting L-DOS47 is safe and capable of modifying TME acidity in NSCLC patients(source).

Where Does L-DOS47 Fit?

L-DOS47 isn’t meant to replace existing therapies but to unlock their full potential. Its value lies in complementing:

  1. Checkpoint inhibitors, by transforming resistant, immunologically “cold” tumors into “hot”, immune-inflamed ones.
  2. Cell therapies (CAR-T, TILs), which currently struggle to persist in acidic environments.
  3. Next-gen antibodies and ADCs, by improving access and engagement within tumors.

Conclusion

The challenge in NSCLC is not only genetic mutations but also the hostile environment tumors create for themselves. Hypoxia and acidosis shield cancer, suppress immunity, and blunt therapy, and countering these barriers could be the missing key to durable responses.

L-DOS47 represents a groundbreaking, tumor-targeted strategy to normalize pH and restore balance in the TME. By lifting the acidic barrier, it prepares the ground for existing and future treatments to achieve their full potential. As development advances, L-DOS47 could become a pivotal ally in reshaping the NSCLC treatment landscape.

References:

1. Molina JR, Yang P, Cassivi SD, Schild SE, Adjei AA. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008 May;83(5):584-94. doi: 10.4065/83.5.584. PMID: 18452692; PMCID: PMC2718421.

2. Binnewies M, Roberts EW, Kersten K, et al. Understanding the tumor immune microenvironment. Nat Med. 2018;24(5):541–50.

3. Corbet C, Feron O. Tumor acidosis: from the passenger to the driver’s seat. Nat Rev Cancer. 2017;17(10):577–93.

4. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall survival with osimertinib in untreated EGFR-mutated NSCLC. N Engl J Med. 2020;382(1):41–50.

5. Wigerup C, Pahlman S, Bexell D. Therapeutic targeting of hypoxia. J Intern Med. 2016;280(6):598–623.

6. Halestrap AP, Wilson MC. The monocarboxylate transporter family—role and regulation. IUBMB Life. 2012;64(2):109–19.

7. Choi Y, Bonfils C, Erlichman C, et al. L-DOS47: a targeted urease immunoconjugate for the modulation of the tumor microenvironment in lung cancer. Cancer Immunol Immunother. 2018;67(11):1879–92.

Jacek Antas

Chief Executive Officer

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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James B. Murphy

Chief Financial Officer

Mr. Murphy is a certified public accountant with over thirty years of experience in finance and operations management. He is currently a consultant with Danforth Advisors LLC (“Danforth”), a leading provider of outsourced strategic and operational specialists across functions in the life sciences industry. While at Danforth, Mr. Murphy has served over fifteen private and publicly held life sciences companies as CFO and CFO Advisor, helping them secure over USD 0.5 billion in financing and successfully execute pivotal asset transactions. Mr. Murphy functions as a consultant to Helix pursuant to a consulting agreement between the Company and Danforth.

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Thomas Mehrling

Medical Adviser

Thomas Mehrling (PhD in Pharmacology and MD) has over 20 years’ experience in multinational Pharma companies developing novel oncology compounds from preclinical research through to registration. Prior to entering the industry, he spent 13 years as an MD at the University Hospital in Frankfurt, working on preclinical and translational projects. He served as Director of European Oncology at Mundipharma International (2003–2013), building the company’s first European oncology business from the ground up out of Cambridge, UK, and completing the clinical development, registration and launch of two major products in Europe, DepoCyte® and Levact® (Ribomustin® and Treanda®). In 2013, he led the establishment of the Mundipharma Group’s start-up, Mundipharma EDO, developing anti-cancer therapeutics for solid tumours out of Basel, Switzerland.

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Kim Gaspar

Director Quality Assurance

Kim is the Director of Quality Assurance at Helix BioPharma Corp. An experienced quality assurance professional with expertise in Canadian, US, and EU regulations, she has been involved in all aspects of Phase I/II biopharmaceutical product development over the years, including regulatory submissions, QC laboratory compliance, tech transfer and third-party oversight of CMC activities, clinical QA, and bioanalytical data analysis. Kim joined Helix in 2000, transitioning into QA in 2003. She holds a B.Sc in Biochemistry and a Ph.D in Veterinary Physiological Sciences, both from the University of Saskatchewan.

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Brenda Lee

Director Clinical Operations

Brenda is the Clinical Operations Director at Helix Biopharma Corp. A clinical research operations professional with 25 years of experience managing clinical trials, ranging from early Phase I to late Phase IIIb/IV studies, she brings experience in clinical study protocol writing and development, trial start-up and vendor management, and a proven track record in planning and managing clinical trials to quality standards, timelines and budget. Brenda joined Helix Biopharma Corp. in 2018, working to advance the clinical program of L-DOS47. She holds B.Sc and M.Sc. degrees from the University of Toronto, specializing in Nutritional Sciences and Human Biology.

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Jerzy Leszczynski

Director

Jerzy Leszczynski is a shareholder of the Company, has spent more than 35 years developing businesses and has served in the capacity of board member of various real estate development companies. Mr. Leszczynski obtained his Master of Science in Chemistry from the Warsaw Institute of Technology.

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Janusz Grabski

Director, Chair of Audit Committee

Janusz (John) Grabski is a lawyer specialized in corporate and real estate law with over twenty years of experience.

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Malgorzata Laube

Director

Malgorzata Laube has over 19 years of experience in nuclear medicine. In her last role with Alberta Health Services, she was the Department Supervisor, Nuclear Medicine at Royal Alexandra Hospital. Ms. Laube obtained a MSc degree in Environmental Engineering from the Warsaw University of Technology and is based in Edmonton, Alberta, Canada.

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Jacek Antas

Chairman of the Board

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

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Jonathan Davis

Advisor, ADC Discovery

Jonathan Davis received his Ph.D. from University of California, San Francisco, where he studied protein structure and function using NMR. After a post-doc at Harvard Medical School exploring RNA selection and structure in the labs of Jack Szostak and Gerhard Wagner, he went to work at EMD Serono, where his work involved improving antibody-based therapeutics, inventing a platform technology for generating heterodimeric Fcs as a basis for multifunctional molecules, and developing a novel scaffold based on an artificially-designed protein from David Baker’s lab. In 2008 he took a job at Bristol-Myers Squibb in Waltham/Cambridge MA, working on antibody discovery and platform development in a wide range of therapeutic areas, with a particular focus on multispecific therapeutics. He moved to Madison, WI in 2019 to take on the role of VP of Innovation and Strategy at Invenra, a biotech focused on bispecific antibodies, and where he is currently head of the Scientific Advisory Board. In early 2024 he left the corporate world to found Creative Antibodies, a consulting firm that helps guide companies to successful antibody discovery and development projects, from mAbs to multispecifics, ADCs, and other formats. Outside of science, Jonathan is a conservatory trained cellist, plays numerous other instruments, and founded the UCSF Orchestra (now Symphony Parnassus) in San Francisco, where he was Music Director for six years.

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Davide Guggi

Advisor, CMC

Davide graduated as a pharmacist and received his PhD in Pharmaceutical Technology and Biotechnology from the University of Vienna. He has over 20 years of experience in the pharmaceutical industry, principally in the field of oncology. At the beginning of his career, Davide led oncology business units and commercial departments at Mundipharma and Gilead across Austria and Eastern Europe. Since over 10 years he has been working as a CMC expert, covering operational and regulatory CMC functions on behalf of over 20 different small- and medium-sized biotech companies across the world. He has served as CMC Director and CSO/CTO for several years, developing both small molecules and biologics (mABs, Fab, ADCs and Radio-immuno-conjugates) from early discovery to NDA/BLA in the US, EU and Canada, with a focus on First-in-Human and Phase I/II studies in oncology indications.

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