Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape
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Updated: Dec 25, 2025
Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Constance J Martin1, Abhishek Datta1, Christopher Littlefield1
1Scholar Rock, Inc., Cambridge, MA 02139, USA.
Abstract:
Despite breakthroughs achieved with cancer checkpoint blockade therapy (CBT), many patients do not respond to anti-programmed cell death-1 (PD-1) due to primary or acquired resistance. Human tumor profiling and preclinical studies in tumor models have recently uncovered transforming growth factor-β (TGFβ) signaling activity as a potential point of intervention to overcome primary resistance to CBT. However, the development of therapies targeting TGFβ signaling has been hindered by dose-limiting cardiotoxicities, possibly due to nonselective inhibition of multiple TGFβ isoforms. Analysis of mRNA expression data from The Cancer Genome Atlas revealed that TGFΒ1 is the most prevalent TGFβ isoform expressed in many types of human tumors, suggesting that TGFβ1 may be a key contributor to primary CBT resistance. To test whether selective TGFβ1 inhibition is sufficient to overcome CBT resistance, we generated a high-affinity, fully human antibody, SRK-181, that selectively binds to latent TGFβ1 and inhibits its activation. Coadministration of SRK-181-mIgG1 and an anti-PD-1 antibody in mice harboring syngeneic tumors refractory to anti-PD-1 treatment induced profound antitumor responses and survival benefit. Specific targeting of TGFβ1 was also effective in tumors expressing more than one TGFβ isoform. Combined SRK-181-mIgG1 and anti-PD-1 treatment resulted in increased intratumoral CD8+ T cells and decreased immunosuppressive myeloid cells. No cardiac valvulopathy was observed in a 4-week rat toxicology study with SRK-181, suggesting that selectively blocking TGFβ1 activation may avoid dose-limiting toxicities previously observed with pan-TGFβ inhibitors. These results establish a rationale for exploring selective TGFβ1 inhibition to overcome primary resistance to CBT.
Insights
Selective inhibition of transforming growth factor-β1 (TGFβ1) with SRK-181 overcomes resistance to cancer checkpoint blockade therapy (CBT). This approach enhances anti-tumor responses and survival without cardiotoxicity, offering a new strategy for non-responsive patients.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Cancer checkpoint blockade therapy (CBT), including anti-programmed cell death-1 (PD-1) antibodies, shows promise but faces primary and acquired resistance in many patients.
- Transforming growth factor-β (TGFβ) signaling is implicated in CBT resistance, but broad inhibition of TGFβ isoforms causes dose-limiting cardiotoxicities.
- Transforming growth factor-β1 (TGFβ1) is the most prevalent TGFβ isoform in human tumors, suggesting it as a key driver of CBT resistance.
Purpose of the Study:
- To investigate whether selective inhibition of TGFβ1 can overcome primary resistance to CBT.
- To evaluate the efficacy and safety of a novel anti-TGFβ1 antibody, SRK-181, in combination with anti-PD-1 therapy.
Main Methods:
- Development of SRK-181, a high-affinity human antibody targeting latent TGFβ1.
- Coadministration of SRK-181 and anti-PD-1 in preclinical mouse models with anti-PD-1-refractory tumors.
- Analysis of tumor immune cell infiltration and assessment of cardiac safety in rat toxicology studies.
Main Results:
- Combined SRK-181 and anti-PD-1 treatment induced significant anti-tumor responses and improved survival in mice with refractory tumors.
- Selective TGFβ1 targeting demonstrated efficacy even in tumors expressing multiple TGFβ isoforms.
- Treatment led to increased intratumoral CD8+ T cells and reduced immunosuppressive myeloid cells.
- SRK-181 showed no observed cardiac valvulopathy in a 4-week rat toxicology study.
Conclusions:
- Selective TGFβ1 inhibition is a viable strategy to overcome primary resistance to cancer checkpoint blockade therapy.
- SRK-181, by selectively targeting TGFβ1, may offer an improved safety profile compared to pan-TGFβ inhibitors, avoiding dose-limiting cardiotoxicities.
- These findings provide a strong rationale for clinical exploration of SRK-181 in combination with anti-PD-1 therapy for patients resistant to CBT.
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