BOT/BAL Offers Novel Immuno-Oncology Combo for Sustained Responses

In an interview with Targeted Oncology, Benjamin Schlechter, MD, senior physician at Dana-Farber Cancer Institute, discusses the promising new combination therapy of botensilimab (BOT) and balstilimab (BAL).

BOT and BAL are 2 distinct immunotherapeutic agents. Each drug plays a crucial, complementary role in orchestrating a robust anticancer immune response.

Botensilimab is an innovative, next-generation cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. Traditional CTLA-4 inhibitors, such as ipilimumab (Yervoy) and tremelimumab (Imjudo), work by disarming an "off switch" on immune T-cells. CTLA-4 is a protein found on the surface of these T cells that, when engaged, helps to downregulate immune activity and prevent an excessive response. By blocking CTLA-4, botensilimab effectively "releases the brakes" on the immune system, promoting T-cell activation and proliferation. This leads to increased inflammation within the tumor microenvironment, with the goal of directing this inflammatory process to eradicate cancer cells.

Unlike its predecessors, botensilimab is an Fc-enhanced anti–CTLA-4 antibody, which means it's engineered to more robustly engage activating Fc receptors on other key immune cells, potentially leading to a more potent and multifaceted antitumor effect. This includes the ability to deplete immunosuppressive regulatory T cells (Tregs) within the tumor, further enhancing the anticancer immune attack.

Balstilimab, the second component of this combination, is a programmed cell death protein 1 (PD-1) inhibitor. PD-1 is another critical immune checkpoint protein, expressed on T-cells. Cancer cells often exploit this pathway by expressing PD-ligand 1 (PD-L1), which binds to PD-1 and effectively tells T cells to leave them alone, acting as a camouflage mechanism. Balstilimab, a fully human monoclonal antibody, specifically blocks this interaction between PD-1 and PD-L1, thus "taking off the mask" of the cancer cells. This reactivates the T-cells, enabling them to recognize and attack the tumor. Well-known FDA-approved PD-1 inhibitors include nivolumab (Opdivo) and pembrolizumab (Keytruda).

The rationale behind combining these 2 agents lies in their synergistic mechanisms of action. Everything in the body's intricate immune system has an "on switch" and an "off switch." Botensilimab acts as a powerful "on switch" for immune activation, igniting the initial inflammatory process against the tumor. However, to sustain this potent anticancer activity, the immune response needs to be prevented from being prematurely shut down. This is where balstilimab comes into play. By blocking the PD-1 pathway, it acts as a "maintainer," ensuring the newly activated T cells remain engaged and continue to fight the cancer.

This strategic BOT/BAL combination is designed to initiate a strong immune response with botensilimab and then sustain that efficacy with balstilimab. Clinical trials, such as the C-800-01 phase 1, open-label, multicenter trial (NCT03860272), have explored various dosing schedules, indicating that only a limited number of botensilimab doses (typically 1 to 4) may be required to kickstart the process, depending on the specific cancer being treated. This initial activation is then followed by a maintenance regimen of balstilimab to ensure durable antitumor effects. This BOT/BAL combination represents a significant advancement over previous generations of CTLA-4 inhibitors that were often used with different maintenance strategies, often involving PD-1 or PD-L1 inhibitors with a less Fc-enhanced CTLA-4 component. The goal is to provide a more comprehensive and sustained immune attack, particularly in tumor types historically resistant to conventional immunotherapies.