Blockade of B7-H1 and PD-1 by Monoclonal Antibodies Potentiates Cancer Therapeutic Immunity

Abstract

Contemporary approaches for vaccination and immunotherapy are often capable of eliciting strong T-cell responses against tumor antigens. However, such responses are not parallel to clinical tumor regression. The development of evasion mechanisms within tumor microenvironment may be responsible for poor therapeutic responses. We report here that constitutive or inducible expression of B7-H1, a B7 family molecule widely expressed by cancers, confers resistance to therapeutic anti-CD137 antibody in mice with established tumors. The resistance is accompanied with failure of antigen-specific CD8+ CTLs to destroy tumor cells without impairment of CTL function. Blockade of B7-H1 or PD-1 by specific monoclonal antibodies could reverse this resistance and profoundly enhance therapeutic efficacy. Our findings support that B7-H1/PD-1 forms a molecular shield to prevent destruction by CTLs and implicate new approaches for immunotherapy of human cancers.

Improved Cancer Immunochemotherapy via Optimal Co-delivery of Chemotherapeutic and Immunomodulatory Agents

“…The immune system plays an important role in cancer initiation and progression . Various mechanisms can be developed by cancer cells to escape from immune surveillance, , such as immune checkpoints, which refer to inhibitory receptors expressed on immune effector cells or immune inhibitory ligands on tumor cells. , Various immune checkpoint molecules have been discovered, such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and others. − Blockade of PD-1 or CTLA-4 using monoclonal antibodies (mAbs) has led to many exciting preclinical and clinical results, as shown by the enhanced and sustained endogenous antitumor immune responses, resulting in durable tumor control. , Despite the successes in some cancer patients, the overall clinical efficacy of the checkpoint blockade is still limited due to the fact that other suppressive mechanisms are also involved in immune escape, such as increased expression of indoleamine 2,3-dioxygenase (IDO). , Another reason is that the efficacy of this treatment is closely associated with pre-existing antitumor immune responses. , Chemotherapy drugs can trigger immunogenic cell death and initiate antitumor immune responses. , The checkpoint blockade can then further enhance and sustain such antitumor immunity. Therefore, one ideal strategy will be to induce immunogenic tumor cell death while simultaneously blocking multiple tumor immunosuppressive pathways.…”

“…5−7 Blockade of PD-1 or CTLA-4 using monoclonal antibodies (mAbs) has led to many exciting preclinical and clinical results, as shown by the enhanced and sustained endogenous antitumor immune responses, resulting in durable tumor control. 8,9 Despite the successes in some cancer patients, the overall clinical efficacy of the checkpoint blockade is still limited due to the fact that other suppressive mechanisms are also involved in immune escape, such as increased expression of indoleamine 2,3-dioxygenase (IDO). 10,11 Another reason is that the efficacy of this treatment is closely associated with preexisting antitumor immune responses.…”

An Anti-Programmed Death-1 Antibody (αPD-1) Fusion Protein That Self-Assembles into a Multivalent and Functional αPD-1 Nanoparticle

“…29 We last examined how well the soluble αPD-1-iTEP fusion and αPD-1 NP inhibit the binding of PD-L1 to the PD-1-positive cells, the working mechanism of PD-1 immune checkpoint therapy. 30,31 To accomplish the examination, we designed and employed a PD-L1 binding inhibition assay. Specifically, we took advantage of the facts that PD-L1-human Fc, a fusion protein of mouse PD-L1 fusion and human IgG Fc, bound with EL4 cells, and that the bound PD-L1-human Fc can be detected by an anti-human Fc antibody.…”

Phase IB Study of GITR Agonist Antibody TRX518 Singly and in Combination with Gemcitabine, Pembrolizumab, or Nivolumab in Patients with Advanced Solid Tumors

“…22). Pembrolizumab and nivolumab are immune checkpoint inhibitors (ICI) that block programmed death-1 (PD-1) and reinvigorate exhausted antitumor CD8 þ T cells within the tumor microenvironment (23)(24)(25). Pembrolizumab and nivolumab produce durable clinical responses and are approved in multiple cancers (26)(27)(28)(29)(30)(31)(32).…”