THOR-707: Retooling a Classic Cancer Fighter to Revolutionize Immunotherapy
A Revolutionary Approach to Boosting the Immune System's Cancer-Fighting Power
When Laura Marston joined a clinical trial in 2019 for her stage four tongue cancer, she was facing daunting odds. Traditional treatments for advanced head and neck cancers had seen little innovation in over two decades, and more than half of patients wouldn't survive to five years. Yet six years later, she marvels, "I am amazed I am still here... this treatment has given me the gift of life." 6
Laura benefited from pembrolizumab, an immunotherapy that helps the immune system recognize and attack cancer cells. While drugs like pembrolizumab have revolutionized cancer treatment, they still fail for many patients—especially those with "cold" tumors that don't attract enough immune cells to mount an effective attack 3 5 . This fundamental limitation has spurred scientists to search for effective combination therapies that can heat up these cold tumors.
Did You Know?
Immunotherapy works by harnessing the body's own immune system to fight cancer, unlike traditional treatments that directly target cancer cells.
Enter THOR-707 (SAR444245), an ingeniously redesigned version of a classic cancer fighter that might hold the key to making immunotherapies work for more patients. This novel compound represents the vanguard of next-generation cancer treatment, harnessing the power of interleukin-2 (IL-2)—a proven but problematic immune stimulant—while avoiding its dangerous side effects 1 3 . Early clinical results suggest this retooled molecule could become a foundation for the next generation of immuno-oncology therapies, potentially helping patients for whom current treatments have failed.
The Double-Edged Sword of IL-2: A Powerful But Flawed Cancer Weapon
To understand why THOR-707 is generating excitement, we need to look back at one of immunotherapy's founding breakthroughs. In 1992, the FDA approved Proleukin (aldesleukin), a recombinant version of IL-2, for metastatic kidney cancer, and later for metastatic melanoma 3 . IL-2 is a powerful cytokine—a signaling molecule that directs immune responses—dubbed a "T-cell growth factor" for its ability to dramatically expand cancer-fighting immune cells.
IL-2 Successes
- Approved for metastatic kidney cancer (1992)
- Approved for metastatic melanoma
- ~7% complete response in renal cell carcinoma
- ~6% complete response in melanoma
IL-2 Limitations
- Severe toxicities including VLS
- Short half-life (13-85 minutes)
- Expands immunosuppressive Tregs
- Requires frequent high-dose administration
The treatment produced remarkable outcomes for a subset of patients, with approximately 7% of metastatic renal cell carcinoma and 6% of metastatic melanoma patients experiencing complete response—essentially being cured of their advanced cancers without further treatment 3 . These unprecedented results proved that the immune system could indeed be harnessed to fight even advanced cancers.
However, IL-2 therapy came with serious challenges that limited its widespread use:
Severe Toxicities
Treatment could cause vascular leak syndrome (VLS), a potentially life-threatening condition where fluids and proteins leak from blood vessels into surrounding tissues 3 .
Short Half-Life
The drug remained in the body for just 13-85 minutes, requiring repeated high-dose administrations that increased toxicity risks 3 .
Conflicting Immune Actions
While IL-2 stimulates cancer-killing CD8 T-cells and natural killer (NK) cells, it also powerfully expands immunosuppressive regulatory T-cells (Tregs) that can actually protect tumors 3 .
This dual nature of IL-2—simultaneously activating anti-cancer forces and the cells that suppress them—made it a therapeutic paradox. Scientists recognized that if they could create a version that selectively enhanced the beneficial effects while minimizing the harmful ones, they might unlock tremendous therapeutic potential.
Engineering a Better IL-2: The Science Behind THOR-707
THOR-707 represents a triumph of modern protein engineering applied to solving the IL-2 paradox. Developed using Sanofi's innovative Synthorx platform (which uses an expanded genetic alphabet to create novel biological compounds), THOR-707 is specifically designed to activate the beneficial immune responses of IL-2 while avoiding its dangerous side effects 1 3 .
The key innovation lies in how the molecule interacts with different components of the IL-2 receptor:
IL-2 Receptor Complex
Consists of three subunits: alpha (CD25), beta, and gamma.
Alpha Subunit
Predominantly found on Tregs (the immune-suppressing cells).
Beta & Gamma Subunits
Primarily on cancer-killing CD8 T-cells and NK cells.
Traditional IL-2 binds strongly to all three subunits, simultaneously activating both helpful and harmful immune cells.
THOR-707 revolutionizes this dynamic through a precise structural modification. Scientists attached a polyethylene glycol (PEG) chain at a specific location on the IL-2 molecule that physically blocks it from binding to the alpha subunit while perfectly preserving its ability to engage with the beta and gamma subunits 1 3 . This "not-alpha" IL-2 thus selectively expands cancer-fighting CD8 T-cells and NK cells without triggering massive Treg expansion or vascular leak syndrome.
| Feature | Traditional IL-2 | THOR-707 |
|---|---|---|
| Binding Profile | Binds all IL-2 receptor subunits | Selective for βγ receptors only |
| Effect on CD8 T-cells & NK cells | Strong expansion | Strong expansion |
| Effect on Tregs | Significant expansion | Minimal expansion |
| Risk of VLS | High | Greatly reduced |
| Half-life | 13-85 minutes | ~10 hours |
| Dosing Frequency | Frequent dosing required | Less frequent dosing |
Table 1: How THOR-707 Improves Upon Traditional IL-2 Therapy
In preclinical studies, this engineered molecule demonstrated striking synergy with anti-PD-1 therapeutics like pembrolizumab 1 3 . The combination proved particularly effective because THOR-703 increases the number and activity of cancer-fighting immune cells, while checkpoint inhibitors like pembrolizumab help ensure these cells can effectively attack tumors.
Inside the HAMMER Trial: Putting THOR-707 to the Test
The promising preclinical data for THOR-707 led to the initiation of the HAMMER trial—an open-label, multicenter Phase 1/2 study designed to evaluate its safety and effectiveness in patients with advanced or metastatic solid tumors 2 . This clinical trial represents a critical step in translating the engineered molecule from laboratory concept to potential cancer therapy.
Trial Methodology
- Phase 1 focused on dose escalation—determining the optimal safe dosage by gradually increasing amounts administered to small patient groups 1 3 .
- Phase 2 expanded to evaluate preliminary efficacy at the recommended dose, examining how well the treatment controlled various cancers 1 .
- The study evaluated THOR-707 both as a monotherapy (alone) and in combination with pembrolizumab, allowing researchers to compare the approaches 1 .
- Primary endpoints included safety, tolerability, and determining the recommended Phase 2 dose, while secondary endpoints examined pharmacokinetics (how the drug moves through the body) and preliminary anti-tumor activity 2 3 .
Patient Population
Participants in the trial had advanced or metastatic solid tumors that had progressed despite standard treatments, representing a patient population with limited options 2 3 . This choice reflects the urgent need for new therapies for those who have exhausted conventional approaches.
Treatment Protocol
Patients in the combination arm received THOR-707 administered intravenously every two weeks alongside standard pembrolizumab treatment 3 . This dosing schedule represented a significant convenience improvement over traditional IL-2 regimens, which often required hospitalization for continuous monitoring during frequent dosing.
The HAMMER trial represents a critical step in translating THOR-707 from laboratory concept to potential cancer therapy, evaluating both safety and effectiveness in patients with advanced solid tumors.
Promising Results: Efficacy and Safety Findings
Interim results from the HAMMER trial, presented in July 2021, provided compelling evidence for both the safety and biological activity of THOR-707 2 3 . The findings offered the first clinical validation that the engineering approach used to create THOR-707 was achieving its intended effects in human patients.
Safety Profile
The safety data revealed a dramatically improved tolerability profile compared to traditional IL-2:
- No dose-limiting toxicities or vascular leak syndrome were observed among the 28 patients evaluated in the interim analysis 3 .
- The absence of VLS was particularly significant, as this side effect had represented a major limitation of traditional IL-2 therapy.
- No anti-drug antibodies against either IL-2 or the PEG component were detected, suggesting the engineered molecule didn't trigger significant immune reactions that could limit its effectiveness 3 .
Biological Activity and Efficacy
Perhaps the most exciting findings came from the pharmacodynamic data, which showed that THOR-703 was successfully activating the intended immune cells:
- CD8 T-cells increased by a median of 3.1-fold after the first treatment cycle, indicating successful expansion of these cancer-fighting cells 3 .
- Natural Killer (NK) cells expanded even more dramatically—by a median of 7.93-fold—and these increases were sustained until the next treatment cycle 3 .
- Critically, Tregs showed only a modest 1.89-fold increase, confirming the selective mechanism of action and representing a dramatically improved ratio of beneficial to suppressive immune expansion compared to traditional IL-2 3 .
| Immune Cell Type | Function in Cancer Immunity | Fold Expansion with THOR-707 |
|---|---|---|
| CD8 T-cells | Primary cancer-killing cells | 3.1x |
| Natural Killer (NK) cells | Recognize and destroy cancer cells | 7.93x |
| Regulatory T-cells (Tregs) | Suppress immune responses | 1.89x |
Table 2: Immune Cell Expansion with THOR-707 Treatment
Among response-evaluable patients, three achieved confirmed partial responses and two additional patients maintained stable disease through multiple treatment cycles 3 . While these numbers came from an early-stage trial focused primarily on safety, they provided promising signals of clinical activity in heavily pretreated patients.
Pharmacokinetic Advantages
The engineering of THOR-707 also achieved significant improvements in its pharmacokinetic profile:
10 hours
Extended half-life of THOR-707
Every 2 weeks
Dosing frequency
The half-life extended to approximately 10 hours, a dramatic improvement over the 13-85 minute half-life of traditional IL-2 3 .
This extended presence in the body allowed for less frequent dosing (every two weeks compared to the multiple daily doses required with traditional IL-2), potentially improving patient quality of life during treatment 3 .
| Parameter | THOR-707 Monotherapy | THOR-707 + Pembrolizumab |
|---|---|---|
| Dose-Limiting Toxicities | None observed | None observed |
| Vascular Leak Syndrome | None observed | None observed |
| CD8 T-cell Expansion | 3.1-fold increase | Data pending |
| NK Cell Expansion | 7.93-fold increase | Data pending |
| Treg Expansion | 1.89-fold increase | Data pending |
| Confirmed Responses | 3 partial responses | Data pending |
| Stable Disease | 2 patients | Data pending |
Table 3: Comparison of Key Clinical Trial Results
The Scientist's Toolkit: Key Technologies Powering Cancer Immunotherapy Advances
The development of THOR-707 and similar innovative therapies relies on a sophisticated array of research tools and technologies. Here are some of the key platforms and approaches driving this field forward:
Protein Engineering Platforms (Synthorx)
Sanofi's expanded genetic alphabet technology enables creation of novel biological compounds with enhanced properties, forming the foundation of THOR-707's development 1 .
PEGylation Technology
The precise attachment of polyethylene glycol chains to therapeutic proteins improves their stability, extends their half-life, and can modify their receptor binding—critical to THOR-707's selective mechanism 3 .
Immune Monitoring Assays
Advanced flow cytometry and single-cell analysis techniques allow researchers to track changes in specific immune cell populations in response to treatment 3 .
Data Analytics & Biomarkers
Advanced computational approaches help identify patient subgroups most likely to respond to specific immunotherapies, enabling personalized treatment approaches.
The Future of Cancer Treatment: Where Do We Go From Here?
The promising early results for THOR-707 represent just one front in the broader revolution in cancer immunotherapy. Researchers are exploring multiple approaches to overcome the limitations of current treatments:
Novel Combinations
Novel combination strategies that pair immune-stimulating agents with checkpoint inhibitors are being actively investigated across the industry 5 . As Dr. Douglas B. Johnson of Vanderbilt University notes, "Novel approaches like TILs, TCR-T therapy, and these neoantigen vaccines are proving grounds in melanoma, but could expand across a variety of cancer types" 5 .
Biomarker Development
Biomarker development remains crucial for identifying which patients are most likely to benefit from specific treatments. Research presented at the 2025 ASCO Annual Meeting demonstrated that combining immunotherapy with drugs like sarilumab (an IL-6 blocker) may help mitigate toxicities associated with aggressive combination approaches 5 .
Next-Gen Cellular Therapies
Next-generation cellular therapies including tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR) therapies are showing response rates of 30-50% even in patients who have progressed on immune checkpoint inhibitors 5 .
The ongoing research into THOR-707 in combination with pembrolizumab continues to evaluate its potential across various cancer types. As Peter Adamson, Sanofi's Global Head of Oncology Development and Pediatric Innovation, stated when the collaboration with Merck was announced: "We believe that THOR-707 has the potential to become a foundation of the next generation of immuno-oncology therapies" 1 .
For patients like Laura Marston, these advances represent more than scientific achievements—they translate to precious additional years of life. As she reflects on her experience: "I was so excited to be on a clinical trial and knowing I was in the best hands was really reassuring... I am amazed I am still here six years later" 6 . It is precisely these transformative outcomes that continue to drive innovation in cancer immunotherapy, offering hope where options were once limited.