e14593 Background: Tumor necrosis factor-alpha (TNF) has well-established anti-tumor effects including cytotoxicity against tumor vasculature. Past use of recombinant TNF to treat solid tumors resulted in unacceptable toxicities when given systemically but is successfully used in localized limb perfusion to treat melanoma and sarcomas. An alternative to promote endogenous TNF-mediated anticancer activity involves therapeutic apheresis to reduce the high concentrations of soluble TNF receptors (sTNF-Rs) produced by tumors, which sequester TNF and inhibit its tumoricidal effects. Methods: The LW-02 Column contains recombinant single-chain TNF, a capture ligand that selectively removes sTNF-Rs from plasma, covalently linked to a bead matrix. LW-02 Column Immunopheresis was evaluated in heavily pretreated patients with metastatic melanoma, renal cell carcinoma or triple negative breast cancer [NCT04142931]. LW-02 Column Immunopheresis was performed 3x/week, processing up to two plasma volumes for approximately 12 weeks as monotherapy (Cohort A, n = 6) or combined with nivolumab (Cohort B, n = 5). The study evaluated column performance, safety, clinical efficacy, and immunological biomarkers in the tumor microenvironment and blood. Results: The LW-02 Column effectively reduced sTNF-R plasma concentrations with capture efficiencies of 95.6% and 82.8% for sTNF-R1 and sTNF-R2, respectively, at the 30-minute procedural time point. At the data cut-off (Sept 30, 2022), median overall survival (OS) was 34.7 and 44.4 weeks for all patients (n = 11) and patients treated for ≥4 weeks (n = 8) (the latter group was prespecified in the protocol), respectively. For Cohorts A and B, median OS was 34.7 weeks and 45.4 weeks, respectively, for patients treated for ≥4 weeks. Evaluation of safety showed that only 2 adverse events (AEs) of 95 total AEs (including 7 SAEs) were deemed possibly related to LW-02 Column treatment. Immunohistochemical evaluation of tumor biopsies obtained 10-14 weeks after initiating LW-02 Column Immunopheresis revealed increased tumor-infiltrating lymphocytes (CD8+, HLA-DR+, and/or PD-1+ cells; 5/5 patients examined), and a reduced presence of tumor-associated macrophages (CD68+; 4/5 patients) compared to pretreatment biopsies. Preliminary immune profiling of peripheral blood mononuclear cells (5 patients) revealed increased expression levels of transmembrane TNF-R1 and TNF-R2, suggestive of increased cellular TNF responsiveness, and increased expression of activation molecules HLA-DR and CD86 after 4 weeks of LW-02 Column monotherapy compared to pretreatment levels. Conclusions: LW-02 Column Immunopheresis achieved safe and effective depletion of sTNF-Rs from plasma of patients with solid tumors. Further studies will assess the clinical benefit profile of the LW-02 Column for resensitizing tumors to respond to immunotherapy. Clinical trial information: NCT04142931 .

Refractory (planetary science)

10.1200/jco.2023.41.16_suppl.e14593

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Supplementary Figure 3 from MYC induces immunotherapy and interferon-γ resistance through downregulation of JAK2

Ettai Markovits Ortal Harush Erez N. Baruch Eldad D. Shulman Assaf Debby

Supplementary Figure 3

10.1158/2326-6066.27026501

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Table S3 from MYC induces immunotherapy and interferon-γ resistance through downregulation of JAK2

Ettai Markovits Ortal Harush Erez N. Baruch Eldad D. Shulman Assaf Debby

Comparison between proteome and transcriptome profiling. Related to Figure 1.

Table (database)

10.1158/2326-6066.27026474.v1

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Supplementary Figure 6 from MYC induces immunotherapy and interferon-γ resistance through downregulation of JAK2

Ettai Markovits Ortal Harush Erez N. Baruch Eldad D. Shulman Assaf Debby

Supplementary Figure 6

10.1158/2326-6066.27026492.v1

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JS1.3 Autoimmune encephalitis as immune related adverse event (irAE) of check point inhibitors (CPI) not so rare as we thought

Neuro-Oncology (2019)

A Taliansky Moran Gadot Damien Urban Jonathan Bar R. Shapira-Frumer

Abstract INTRODUCTION CPI has significant efficacy and toxicities. We describe our experience with CPI treated patients diagnosed with irAE encephalitis. METHODS Patients treated with CPI during 2017–2018 were identified from institute’s EMR. Patients treated for irAE encephalitis were identified from the database of the Neuro-Oncology Unit of the Institute. Results: Eleven patients were diagnosed with irAE encephalitis out of 1500 treated with CPI at the Institute (0.73%). Four patients had NSCLC, 3 had melanoma, the one patient had each of SCLC, uterine carcinoma, RCC and breast cancer. Median age was 69 years (49–87). Four of 11 were treated with chemo-CPI, 3-with CPI combinations. Median onset of symptoms was at 19 days (5–180) following initial treatment. All events were high grade severity. Eight patients fully recovered after immunotherapy discontinuation and steroid treatment, of these, 2 melanoma patients underwent uncomplicated CPI re-challenge. Three patients, all non-melanoma, had severe neurological sequelae. Two of them were treated with steroids, PLEX and cyclophosphamide: one improved neurologically although died 6 months later from cancer. One patient was oncologically stable but died from neurological deterioration 7 months later. The additional patient was treated with steroids only because his advanced age and decease in hospice 2 months later. CONCLUSION Encephalitis, as an irAE of CPI, seems to be more common and severe than previously thought, predominantly in non melanoma patients. Nevertheless, in the majority of cases it is reversible and in some melanoma patients immunotherapy re-challenge is safe. Future studies will have to define risk factors and severity prediction.

Discontinuation

Autoimmune encephalitis

10.1093/neuonc/noz126.012

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Supplementary Figure 3 from MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2

Ettai Markovits Ortal Harush Erez N. Baruch Eldad D. Shulman Assaf Debby

Supplementary Figure 3

10.1158/2326-6066.23627578.v1

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Table S2 from MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2