Polymicrobial sepsis alters the adaptive immune response and induces T cell suppression and Th2 immune polarization. We identify a GR-1+CD11b+ population whose numbers dramatically increase and remain elevated in the spleen, lymph nodes, and bone marrow during polymicrobial sepsis. Phenotypically, these cells are heterogeneous, immature, predominantly myeloid progenitors that express interleukin 10 and several other cytokines and chemokines. Splenic GR-1+ cells effectively suppress antigen-specific CD8+ T cell interferon (IFN) γ production but only modestly suppress antigen-specific and nonspecific CD4+ T cell proliferation. GR-1+ cell depletion in vivo prevents both the sepsis-induced augmentation of Th2 cell–dependent and depression of Th1 cell–dependent antibody production. Signaling through MyD88, but not Toll-like receptor 4, TIR domain–containing adaptor-inducing IFN-β, or the IFN-α/β receptor, is required for complete GR-1+CD11b+ expansion. GR-1+CD11b+ cells contribute to sepsis-induced T cell suppression and preferential Th2 polarization.

To the Editor: A 48-year-old woman being treated with lenalidomide for kappa light chain multiple myeloma presented with severe rash associated with urticaria, pruritus, and fever. The patient was initially diagnosed with Stage II breast cancer (ER/PR+ and HER-2neu negative) in 2003 and underwent treatment with lumpectomy followed by four cycles of Adriamycin and Cyclophosphamide followed by two cycles of Paclitaxel and then switched to an additional two cycles of Taxotere because of poor tolerance. This was followed by radiation therapy and hormonal therapy. Two years later she was diagnosed with multiple myeloma. As a result of her negative prior experience with chemotherapy and steroids she refused treatment with either and was therefore initially treated with single agent thalidomide. Thalidomide treatment had to be discontinued due to a similar reaction manifesting with severe rash, urticaria, and pruritus, which was thought to be a Type I (IgE mediated) hypersensitivity reaction. When lowered to 50 mg the patient continued to experience side effects necessitating its permanent discontinuation. She was subsequently treated with bortezomib which had to be discontinued secondary to increasing neuropathy. Lenalidomide treatment at the standard dose of 25 mg resulted in the reaction described above which was similar to the reaction she developed on thalidomide, which is not surprising given the structural similarities between the two drugs. The patient was subsequently referred to Allergy-Immunology for desensitization in August 2006. The patient was desensitized using the protocol shown in Table I. In brief, lenalidomide was dissolved in normal saline and diluted to concentrations of 0.025, 0.25, and 2.50 mg/ml. She was given gradually increasing strengths to take orally at 15-to 20-min interval. During the desensitization she had her blood pressure, heart rate, temperature, pulse oximetry, and peak flow monitored. She tolerated the escalating doses with no reaction and was subsequently begun on lenalidomide 15 mg daily, and continues to tolerate daily continuous dosing with no evidence of recurrent hypersensitivity. The patient remains asymptomatic in a PR as defined by the International Working Group Uniform Response Criteria, and also remains free from any evidence of recurrent breast cancer. This represents the first case of successful desensitization to lenalidomide that we are aware of. Since this drug has become an integral component of multiple myeloma therapy this represents an important option for patients who otherwise would not be able to tolerate lenalidomide.

No abstract

Immunotoxins (the fusion of a bacterial cytotoxic protein with a targeting moiety) have been explored since the 1970s but have been limited in their therapeutic utility because of the propensity to drive a host innate immune response resulting in potentially fatal cytokine elevations and capillary leak syndrome (CLS). Engineered Toxin Bodies (ETBs) represent an important evolution in immunotoxins, overcoming the issues with innate immunity and adding biologic utility not previously seen. ETBs use an antibody-based targeting domain genetically fused to a de-immunized form of the Shiga-like toxin A subunit (SLTA). Like previous immunotoxins, ETBs bind and induce cell-death in a target-specific manner but have additional biology not inherent to other immunotoxins. ETBs can induce their own internalization, allowing for the targeting of poorly/non internalizing receptors. ETBs can deliver other payloads like viral class I antigen or small molecules in addition to SLTA, allowing for multiple MOAs. And, most importantly, we have de-immunized SLTA through genetic engineering to create ETBs devoid of innate immune effects/CLS seen with previous immunotoxins. Three ETBs (MT-0169, MT-5111, and MT-6402) are currently in clinical studies across different targets (CD38, HER2, PD-L1) and across hematologic malignancies, solid tumor, and immuno-oncology indications. To date, no clinical manifestations of CLS have been observed in 80+ patients; in contrast, the rate of CLS for approved immunotoxins ranges for 33% to >50%. In general, all three ETBs have shown good tolerability with little off-target toxicity and all three ETBs have shown monotherapy clinical benefit in heavily pre-treated patients. MT-6402, an ETB targeting PD-L1, is the first ETB to carry the additional mechanism of antigen seeding. Along with its ability to destroy ribosome in a PD-L1-targeted fashion, MT-6402 can deliver a class I antigen derived from human cytomegalovirus (CMV) to the ER, allowing for presentation of the antigen in complex with MHC class I on the cell surface of a tumor cell. Early clinical data demonstrate antigen seeding with MT-6402 can result in T-cells specific to the seeded CMV antigen mounting an immune response to the tumor. ETBs represent a unique and wholly distinct scaffold for drug development in oncology. ETBs allow for the targeting of non-internalizing receptors that are not amenable to ADCs. ETBs have a mechanism of cell-kill (enzymatic and irreversible ribosomal destruction) that is distinct from any approved agent in oncology. ETBs can also deliver additional payloads to drive unique biology like the alteration of tumor immunophenotype. Here we describe three active clinical stage programs with encouraging safety and efficacy data that represent a transformation of the immunotoxin landscape into a more viable therapeutic approach to target validated as well as typically intractable clinical cancer targets. Citation Format: Chris Moore, Lee Robinson, Garrett Cornelison, Joseph Dekker, Roger Waltzman, John Majercak, Joseph Phillips, Jay Zhao, Jason Kim, Eric Poma. Engineered Toxin Bodies (ETBs): Clinical stage immunotoxins with a safer and differentiated profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2661.