Delivering preclinical data for combined radiotherapy and chemotherapy strategies in oncology

Using our Xstrahl CIX3 cabinet irradiator, we have established robust murine tumor models that generate high-quality preclinical data to evaluate the effectiveness of combining radiotherapy with anti-cancer drug therapies.

In this article we discuss the subject and refer to a recent example from a study where we investigated using radiotherapy in combination with immune checkpoint inhibitors (ICIs) (Figure 1).

These type of programs are further strengthened by our in-house capabilities for pharmacokinetic (PK), target engagement and pharmacodynamic (PD) analyses, enabling us to generate comprehensive data packages that support oncology drug discovery programs.

Unlocking the potential of combined radiotherapy and immunotherapy

Over the past decade, immune checkpoint inhibitors have transformed the cancer treatment landscape [1]. By targeting key immune regulatory pathways on T cells, these antibody-based therapies can activate anti-tumor immune responses, delivering durable clinical benefit—and in some cases long-term remission—to patients across a range of cancer types.

Today, more than 80 FDA approvals exist for immune checkpoint inhibitors used either as monotherapies or in combination regimens. Their success has demonstrated the remarkable therapeutic potential of mobilizing the immune system against cancer.

The caveat: Intrinsic and acquired resistance

Despite these advances, significant challenges remain. Both intrinsic and acquired resistance present huge clinical barriers as they limit the effectiveness of immunotherapy, with only around 20% of patients achieving meaningful responses to single-arm therapy with a checkpoint inhibitor [2]. In addition, reliable biomarkers capable of predicting treatment response remain elusive.

As a result, there is strong interest in identifying combination strategies that can expand the proportion of patients who benefit from immunotherapy.

Why combine radiotherapy with immunotherapy?

Radiotherapy is well established as a cornerstone of cancer treatment, primarily through its ability to induce tumor cell death. However, accumulating evidence shows that irradiation can also remodel the tumor immune microenvironment [3], [4].

As tumor cells are damaged or ultimately die following irradiation, they release tumor-associated antigens, growth factors, cytokines and chemokines that can stimulate immune activation and promote cytotoxic T-cell infiltration into tumors [3], [4]. This immune-modulating effect provides a compelling rationale for combining radiotherapy with immune checkpoint inhibitors, with the goal of enhancing anti-tumor immunity and overcoming resistance mechanisms [5], [6].

The importance of preclinical models

A growing number of clinical trials are evaluating radiotherapy-immunotherapy combinations across multiple cancer indications [4]. Early-phase studies have demonstrated encouraging safety profiles, and attention is now focused on determining which treatment regimens deliver the greatest clinical benefit.

Several critical variables require evaluation and optimization, including:

• Tumor type and tissue of origin
• Disease stage
• Treatment setting (first-line, neoadjuvant or adjuvant)
• Radiation dose and fractionation schedule
• Drug sequencing and treatment timing

Preclinical models play a vital role in answering these questions before therapies progress into clinical development.

Radiotherapy Models at Sygnature Discovery

Within Sygnature Discovery’s Translational Oncology Department, we have developed a range of syngeneic and human xenograft mouse models using the Xstrahl CIX3 cabinet irradiator. This platform enables precise delivery of targeted X-ray irradiation directly to tumors, allowing evaluation of radiotherapy both as a standalone treatment and in combination with existing or novel therapeutic agents.

Using these models, we can compare

• Single high-dose radiation administration
• Fractionated low-dose regimens

The latter more closely reflects radiotherapy protocols commonly used in clinical practice.

Assessing the abscopal effect

Our models also enable evaluation of the abscopal response, an important phenomenon in which irradiation of one tumor leads to anti-tumor effects at distant, non-irradiated tumor site. Monitoring these responses provides valuable insight into the systemic immune effects of treatment combinations.

Generating rich mechanistic data

To maximize study value, we complement efficacy assessments with extensive ex vivo analyses of tumor and host tissues.

Our pharmacodynamic capabilities include:

• Multi-parameter flow cytometry to characterize tumor-infiltrating immune cells and systemic immune responses
• Gene expression analysis
• Protein expression profiling

Combined with our PK and target-engagement expertise, these approaches deliver a detailed mechanistic understanding of therapeutic activity.

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CASE STUDY

Radiotherapy Combined with Immune Checkpoint Inhibition

We have established and characterized murine tumor models to evaluate the effects of radiotherapy in combination with immune checkpoint inhibitors.

For further details, read the full case study here.

Summary

Cancer is a highly complex disease driven by interactions between the multiple types of tumor cells and the surrounding microenvironment. To identify effective new treatments, researchers require predictive and informative preclinical models capable of evaluating novel therapeutics both alone and in combination with radiotherapy.

Radiotherapy remains a fundamental component of cancer care, but its value extends beyond direct tumor cell killing. By reshaping the tumor immune microenvironment, radiotherapy has emerged as a powerful partner for immunotherapies and other targeted anti-cancer agents.

Through the use of Xstrahl CIX3 cabinet irradiator, we have established advanced murine models that generate critical preclinical data to support combined radiotherapy and cancer drug development strategies. Furthermore, we are able to augment these studies by performing PK, target engagement and PD analyses, generating comprehensive data packages that accelerate decision-making and de-risk oncology drug discovery programs.

References

[1]         P. Sharma et al., “Immune checkpoint therapy—current perspectives and future directions,” Cell, vol. 186, no. 8, pp. 1652–1669, Apr. 2023, doi: 10.1016/j.cell.2023.03.006.

[2]         Public Health England, “Chemotherapy, Radiotherapy and Surgical Tumour Resections in England,” https://www.gov.uk/government/statistics/chemotherapy-radiotherapy-and-surgical-tumour-resections-in-england/chemotherapy-radiotherapy-and-surgical-tumour-resections-in-england.

[3]         H. E. Barker, J. T. E. Paget, A. A. Khan, and K. J. Harrington, “The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence,” Nat. Rev. Cancer, vol. 15, no. 7, pp. 409–425, Jul. 2015, doi: 10.1038/nrc3958.

[4]         M. McLaughlin et al., “Inflammatory microenvironment remodelling by tumour cells after radiotherapy,” Nat. Rev. Cancer, vol. 20, no. 4, pp. 203–217, Apr. 2020, doi: 10.1038/s41568-020-0246-1.

[5]         W. Kim, H. Kim, W. Il Jang, M. S. Kim, and S. H. Bae, “Radiotherapy Combined with Immune Checkpoint Inhibitor on Murine Fibrosarcoma and a Narrative Review of Clinical Studies.,” Curr. Issues Mol. Biol., vol. 48, no. 1, Dec. 2025, doi: 10.3390/cimb48010020.

[6]         C. Lynch, S. P. Pitroda, and R. R. Weichselbaum, “Radiotherapy, immunity, and immune checkpoint inhibitors,” Lancet Oncol., vol. 25, no. 8, pp. e352–e362, Aug. 2024, doi: 10.1016/S1470-2045(24)00075-5.