CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1.
As severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) evolves to escape natural antibodies, it also loses sensitivity to therapeutic antibody drugs. By contrast, evolution selects for binding to ACE2, the cell-surface receptor required for SARS-CoV-2 infection. Consistent with this, we find that an ACE2 decoy neutralizes antibody-resistant variants, including Omicron, with no loss in potency. To identify design features necessary for in vivo activity, we compare several enzymatically inactive, Fc effector-silenced ACE2-Fc decoys. Inclusion of the ACE2 collectrin-like domain not only improves affinity for the S protein but also unexpectedly extends serum half-life and is necessary to reduce disease severity and viral titer in Syrian hamsters. Fc effector function is not required. The activity of ACE2 decoy receptors is due, in part, to their ability to trigger an irreversible structural change in the viral S protein. Our studies provide a new understanding of how ACE2 decoys function and support their development as therapeutics to treat ACE2-dependent coronaviruses.
e15134 Background: We use a decision analytic model to project the effectiveness and cost burden of microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) treatment in the era of immunotherapy. Methods: We simulated the treatment of hypothetical patients with MSI-H/dMMR mCRC in two scenarios: patients refractory to two lines of chemotherapy, or untreated. We compared nivolumab, ipilimumab/nivolumab, trifluridine/tipiracil (third-line) and mFOLFOX6/cetuximab (first-line) based on the CheckMate 142, RECOURSE, and CALGB/SWOG 80405 trials. Results: Ipilimumab/nivolumab was the most effective strategy in both third- and first-line settings, and both checkpoint inhibitor therapies were more effective than chemotherapy (Table 1). However, neither checkpoint inhibitor therapy was cost-effective compared to chemotherapy in the base case due to maintenance nivolumab drug cost. Ipilimumab/nivolumab could be the most cost-effective strategy in both settings if treatment duration were limited to two years. Conclusions: Checkpoint blockade is significantly more effective for MSI-H/dMMR mCRC compared to third- and first-line chemotherapy, but is not cost-effective in either setting due to drug costs. Decreases in duration of maintenance nivolumab could make ipilimumab/nivolumab cost-effective. THERAPY COST, US$| UNADJ.LYs| QALYs| ICER, US$/QALY Third-line therapy Base case Trifluridine/tipiracil 90,700 0.74 0.07 Nivolumab 1,113,400 8.21 6.76 153,000 Ipilimumab/nivolumab 1,519,200 10.69 9.25 162,700 Treatment limited to two years Trifluridine/tipiracil 90,700 0.74 0.07 Nivolumab 264,000 8.21 6.76 Weakly dominated Ipilimumab/nivolumab 298,900 10.69 9.25 22,700 First-line therapy Base case mFOLFOX6/cetuximab 388,400 2.72 1.63 Nivolumab 1,196,600 8.21 7.00 150,700 Ipilimumab/nivolumab 1,583,900 10.69 9.44 158,700 Treatment limited to 2 years mFOLFOX6/cetuximab 388,400 2.72 1.63 Strongly dominated Nivolumab 347,170 8.21 7.00 Ipilimumab/nivolumab 363,700 10.69 9.44 6,800 LY = life-years
B-cell lymphomas express a functionally active and truly tumor-specific cell-surface product, the variable region of the B-cell receptor (BCR), otherwise known as idiotype. The tumor idiotype differs, however, from patient to patient, making it a technical challenge to exploit for therapy. We have developed a method of targeting idiotype by using a semisynthetic personalized therapeutic that is more practical to produce on a patient-by-patient basis than monoclonal antibodies. In this method, a small peptide with affinity for a tumor idiotype is identified by screening a library, chemically synthesized, and then affixed to the amino terminus of a premade IgG Fc protein. We demonstrate that the resultant semisynthetic anti-idiotype peptibodies kill tumor cells in vitro with specificity, trigger tumor cell phagocytosis by macrophages, and efficiently clear human lymphoma in a murine xenograft model. This method could be used to target tumor with true precision on a personalized basis.
Abstract The complementarity determining region, or idiotype, of the surface immunoglobulin receptor is a true tumor-specific marker on B-cell lymphomas unique to each patient. Antibodies against idiotype can induce complete regression of lymphoma in patients, but since this requires the generation of a custom monoclonal antibody for each patient, it has not been practical. We have developed a method for targeting idiotype using a novel construct that we refer to as a “semi-synthetic peptibody”. It consists of a synthetic peptide ligand for idiotype that is covalently linked to the amino terminus of a recombinant IgG Fc domain. Peptide ligands for idiotype can be identified by high throughput screens of random peptide libraries and produced inexpensively by solid-phase synthesis. Linkage of these idiotype ligands to the Fc domain enhances their pharmacokinetics and augments their anti-tumor effect by activating innate immune effectors. Since each patient-specific synthetic peptide can be chemically linked to a common IgG Fc domain, this modular design yields a custom therapeutic that may be more practical to produce than a unique biologic monoclonal antibody. We demonstrate that semi-synthetic peptibodies bind specifically to the idiotype of tumor cells and induce apoptosis by crosslinking surface immunoglobulin. Additionally, they trigger antibody dependent cellular cytotoxicity, antibody mediated phagocytosis, and complement-mediated lysis of opsonized lymphoma cells in vitro. They possess a favorable pharmacokinetic profile and are sufficient to clear tumor in SCID mice challenged intravenously with a luciferase-labeled human lymphoma cell line. Tumor clearance in vitro and in vivo mediated by peptibody was superior to that achievable with an anti-idiotype monoclonal antibody. Thus, semi-synthetic anti-idiotype peptibodies demonstrate multimodal activity against lymphoma cells in vitro and clear human lymphoma in a disseminated xenograft model. This modular, semi-synthetic design may enable a personalized and targeted therapy that is feasible to produce for patients with B-cell lymphoma. Citation Format: James Torchia, Patrick Ng, Homer Chen, Kipp Weiskopf, Ronald Levy. Semi-synthetic peptibodies are a novel personalized therapeutic with activity against lymphoma in vitro and in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 648. doi:10.1158/1538-7445.AM2014-648
Activation of TLR9 by direct injection of unmethylated CpG nucleotides into a tumor can induce a therapeutic immune response; however, Tregs eventually inhibit the antitumor immune response and thereby limit the power of cancer immunotherapies. In tumor-bearing mice, we found that Tregs within the tumor preferentially express the cell surface markers CTLA-4 and OX40. We show that intratumoral coinjection of anti-CTLA-4 and anti-OX40 together with CpG depleted tumor-infiltrating Tregs. This in situ immunomodulation, which was performed with low doses of antibodies in a single tumor, generated a systemic antitumor immune response that eradicated disseminated disease in mice. Further, this treatment modality was effective against established CNS lymphoma with leptomeningeal metastases, sites that are usually considered to be tumor cell sanctuaries in the context of conventional systemic therapy. These results demonstrate that antitumor immune effectors elicited by local immunomodulation can eradicate tumor cells at distant sites. We propose that, rather than using mAbs to target cancer cells systemically, mAbs could be used to target the tumor infiltrative immune cells locally, thereby eliciting a systemic immune response.
Abstract Background: CD4+CD25+FOXP3+ regulatory T-cells (Tregs) infiltrate all tumor sites and play a central role in maintaining immune tolerance to cancers. Scientific question: Is the local immunomodulation of Tregs from a single tumor site sufficient to trigger a systemic anti-tumor immune response able to eradicate distant tumor sites ≤ Results: We found that tumor infiltrating Tregs preferentially express CTLA4 (CD152) and OX40 (CD134) compared to their counterparts in the blood and other lymphoid organs, both in mice and in human lymphomas. We show in a murine lymphoma model that OX40 and CTLA4 upregulation occurs specifically on Tregs directed against tumor antigens. Injections of low doses of anti-CTLA4 and anti-OX40 together with CpG, a TLR-9 agonist, directly into a single tumor site depletes the Tregs from the injected tumor but not from distant ones. This immunomodulation subsequently triggers an anti-tumor immune response able to cure mice with established disseminated disease. This triple combination is uniquely required as neither CpG alone nor mAbs without CpG are effective. Significance: immunomodulatory antibodies are currently under clinical development for cancer therapy. Their major toxicity is the triggering of auto-immune diseases. We show here that after injections of very little doses of these antibodies with CpG at one tumor site, their serum levels become undetectable. However, these doses are sufficient to trigger a systemic anti-tumor response able to eradicate distant sites. Impact: we recently have published positive results of intra-tumoral CpG in patients with follicular Lymphoma (Brody, Levy, et al. JCO, 2010). Anti-CTLA4 has just been approved by the FDA/EMEA in patients with metastatic melanoma. Anti-Ox40 antibodies are currently being tested in phase I/II clinical trials. Therefore, the combination described here can be tested in patients with injectable sites of lymphoma. Together, these results are in favor of a paradigm shift in cancer therapy where the immune system is targeted rather than the tumor itself. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-139. doi:1538-7445.AM2012-LB-139
