Cancer Immunotherapy Platform Technology

Biothera’s clinical candidate, Imprime PGG, is a novel dectin receptor agonist. Mechanistically, Imprime PGG reverses tumor-mediated immunosuppression and promotes antigen presentation, eliciting the activation and subsequent infiltration of tumor-specific, killer T cells into tumor tissues. In preclinical tumor models, Imprime PGG-mediated immune responses enhance the anti-cancer efficacy of immune checkpoint inhibitors and potentially other cancer immunotherapies. Imprime PGG is currently in a series of phase 2 clinical studies in combination with immune checkpoint inhibitors to assess whether Imprime PGG might extend and enhance the clinical benefit of immune checkpoint inhibitor therapy. Primary data from a phase 2 study evaluating Imprime PGG and Merck’s Keytruda® in triple negative breast cancer patients validate this therapeutic approach.

The Anti-Cancer Immune Response. An effective anti-cancer immune response involves the integrated action of both the innate and adaptive arms of the immune system. Activated Innate immune cells can kill cancer cells directly and can also dictate the state of the tumor microenvironment. In addition, specialized cells of the innate immune system—antigen presenting cells (APCs)—are critically responsible for educating and activating T cells to tumor antigens. These activated, tumor-specific T cells can seek out and kill even widely disseminated, metastatic cancers. These T cells also retain immune memory for long-term disease control.

Cancers Actively Preclude or Evade T Cell Attack. Cancers can evade T cell-mediated destruction by preventing T cell activation or by extinguishing killing by activated T Cells. Cancers make growth factors, cytokines and chemokines that instruct innate immune (i.e. myeloid) cells to exist in a wound-healing (M2) state. While promoting tissue repair and regrowth, these M2-state myeloid cells restrict APC function and subsequent T cell activation.  Alternately, cancers can evade T cell killing by expressing the PD-L1 checkpoint protein, which binds the PD-1 receptor on activated T cells, sending a “do not kill” signal to the T cells.

CPIs Restore T Cell-Mediated Tumor Killing. CPIs (KEYTRUDA®, Tecentriq®) block the PD-L1:PD-1 interaction, unleashing activated T cells on cancer cells. These CPIs have revolutionized cancer therapy, providing long-term disease control. Unfortunately, the majority of cancer patients do not realize clinical benefit from CPIs, often because, in these patients, the immunosuppressive microenvironment precludes T cell activation. Without activated T cells, CPIs are ineffective.

Rationale for Imprime PGG in Combination with CPI Therapy. Mechanistic studies reveal that Imprime PGG specifically binds the dectin receptor, reversing tumor-mediated immunosuppression, and activating APCs to promote tumor-specific T cell activation. Accordingly, Imprime PGG enhances CPI efficacy in multiple preclinical tumor studies.  A brief video summarizes Imprime PGG’s unique mechanism of action in combination with checkpoint inhibitor therapy.

Distinct Properties of Imprime PGG. The innate immune system recognizes “non-self danger” signals through a series of pattern recognition receptors (PRRs) to trigger immune responsiveness. Agonists of these PRRs, which include Toll-like Receptors (TLRs), cGAS-STING and RIG-I, are in clinical development with CPIs. These PRR agonists can stimulate APC function and subsequent T cell activation. Unlike Imprime PGG, it is unclear whether these agents can affect tumor-mediated immunosuppression. Moreover, these agents can spark life-threatening cytokine storms and are typically dosed by direct intra-tumor injection to avoid this systemic toxicity. By contrast, Imprime PGG is a “danger signal” for the distinct PRR, DECTIN. Imprime PGG is safely delivered systemically by IV infusion (~600 human subjects dosed to date).