Project

BOT+BAL Combines Complementary Immune Mechanisms to Target Tumors Historically Resistant to Immunotherapy

Agenus

DOI: 10.26303/44ac-zc96

Key takeaways

  • BOT is a multifunctional, Fc-enhanced anti-CTLA-4 antibody designed to promote T-cell priming, engage antigen-presenting and myeloid cells, reduce intratumoral regulatory T cells, and support immune memory.
  • BAL blocks PD-1 signaling to help sustain the function of tumor-reactive T cells after immune activation.
  • By combining complementary mechanisms, BOT+BAL is designed to convert immunologically “cold” tumors into “hot,” immune-active tumors and extend the potential benefits of immunotherapy to cancers that have historically responded poorly to conventional immunotherapies.

What is it about?

Botensilimab plus balstilimab (BOT+BAL) is an investigational immunotherapy combination designed to activate and sustain a broad immune response against cancer, including in immunologically “cold” tumors that have historically responded poorly to conventional immunotherapies.

Botensilimab (BOT) is a multifunctional, Fc-enhanced anti-CTLA-4 antibody. In addition to blocking CTLA-4 signaling to promote T-cell priming and expansion, BOT has an engineered Fc region designed to enhance engagement with activating Fc gamma receptors in the tumor microenvironment. This differentiated design is intended to reduce intratumoral regulatory T cells, activate antigen-presenting and myeloid cells, and promote immune memory while reducing complement-mediated toxicities associated with conventional CTLA-4 inhibition.

Balstilimab (BAL) is a fully human anti-PD-1 antibody. It prevents PD-1 from interacting with its ligands, PD-L1 and PD-L2, blocking an inhibitory signal that tumors can use to suppress T-cell activity. By inhibiting this pathway, BAL is intended to help sustain the function of tumor-reactive T cells after they have been primed and activated.

BOT+BAL target complementary stages of the antitumor immune response. Together, these complementary mechanisms are designed to reshape the tumor microenvironment and convert immunologically “cold” tumors into “hot,” immune-active tumors that may be more responsive to immune attack. This may be particularly relevant in microsatellite-stable/mismatch repair-proficient (MSS/pMMR) tumors, which have historically derived limited benefit from conventional immunotherapy.

Why is it important?

Immunotherapies have transformed the treatment of many cancers, with the greatest activity generally observed in immunologically “hot” tumors characterized by pre-existing immune recognition and T-cell infiltration. Their activity remains limited in immunologically “cold” tumors, where insufficient immune recognition, limited T-cell infiltration, and an immunosuppressive tumor microenvironment can restrict responses to PD-1 blockade alone and to conventional CTLA-4 and PD-1 combinations.

Microsatellite-stable and mismatch repair-proficient (MSS/pMMR) tumors are an important example. MSS/pMMR colorectal cancers represent the large majority of colorectal cancers (85-95%) and have historically shown limited responsiveness to conventional immunotherapies.

BOT+BAL is designed to address several components of immune resistance. BOT promotes T-cell priming while engaging additional immune cells within the tumor microenvironment, and BAL helps preserve the activity of the resulting tumor-reactive T cells. This provides the scientific rationale for investigating the combination in MSS/pMMR tumors and other cancers that have historically been difficult to treat with immunotherapy.

Clinical studies have demonstrated deep and durable antitumor activity with BOT+BAL across multiple tumor types and treatment settings, including in patients with advanced, treatment-refractory cancers. These findings provide clinical evidence that the combination’s differentiated mechanism can generate meaningful immune activity in tumors that have historically responded poorly to conventional immunotherapy.

Ongoing and planned studies are investigating whether this activity translates into improved long-term outcomes in larger patient populations. Click on the next story below – Long-Term Survival and Safety Data for BOT+BAL in Refractory MSS Metastatic Colorectal Cancer – to examine the clinical evidence supporting BOT+BAL in advanced, treatment-refractory disease.

Page published: 12-Nov-2026

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Who is involved?

Important information

In October 2026, BOT+BAL reached an important milestone with its first marketing authorizations in Armenia, where Botvymo® (botensilimab) and Evamplix® (balstilimab) were approved for use in combination in eligible adults with microsatellite-stable (MSS) metastatic colorectal cancer without active liver metastases who have previously received available standard therapies.

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