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Sukhmani Kaur Padda
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MA 16 - Mediastinal, Tracheal and Esophageal Tumor: Multimodality Approaches (ID 675)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:K. Shibuya, Francoise Mornex
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 313 + 314
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MA 16.01 - Characterization of Autoantibody Responses in Thymoma with Myasthenia Gravis by Single-Cell Sequencing of B-cells (ID 8351)
15:45 - 15:50 | Presenting Author(s): Sukhmani Kaur Padda
- Abstract
- Presentation
Background:
Thymomas are frequently associated with paraneoplastic autoimmune syndromes, with the most common being Myasthenia Gravis (MG). MG is characterized by autoantibodies against muscle antigens, most frequently the acetylcholine receptor (AChR). Patients with thymoma also present with autoantibodies against striational muscle proteins (STR-Abs), such as the sarcomeric protein titin and the ryanodine receptor. These autoantibodies have been primarily regarded as diagnostic or prognostic markers, but little is known about their pathological mechanisms. Comprehensive mechanistic studies have been hindered by the lack of patient-derived monoclonal antibodies (mAbs). Such mAbs could help to define immunogenic epitopes in known or novel autoantigens, and would be useful for deciphering pathological mechanisms in vitro or in animal models.
Method:
We studied mAbs derived from a patient with thymoma and MG, with the patient’s written informed consent and under a Stanford IRB approved protocol. The patient had Masaoka-Koga stage II type B2 thymoma, with multiple recurrences over a period of 8 years. The patient’s MG symptoms included fatigable muscle weakness, the presence of anti-AChR antibodies, and high titer STR-Abs. The patient also had myositis with muscle-related symptoms worsening after thymectomy. We sequenced the repertoire of the patient’s plasmablasts, which are antibody-producing cells derived from the activated B-cell clones, using a barcode-based method for sequencing single-cell immunoglobulin genes developed in our lab. We then expressed 26 mAbs from clonally expanded families of antibodies from two different timepoints that are six months apart. The first timepoint was two years post-Rituximab, coinciding with a tumor recurrence and slow progression of muscle weakness. The second timepoint was a month after radiotherapy when the patient was admitted with severe muscle weakness and pain. Treatment included plasmapheresis/IVIG and Rituximab, with limited improvement over the weeks following hospitalization. The patient was on steroids at both timepoints. Anti-Titin serum antibody titers increased by 60% between these two timepoints.
Result:
Two of the mAbs that were expressed reacted with the main immunogenic region of titin in ELISA, and one of the clones was present at both of the timepoints investigated. These clones were detected despite B-cell depletion by treatment with Rituximab.
Conclusion:
Our results suggest that (i) sequencing single-cell immunoglobulins is a powerful technique for isolating and functionally characterizing mAbs against autoantigens in thymoma and that (ii) persisting or recurring autoreactive clones in patients with thymoma, such as anti-titin clones, may be associated with refractory paraneoplastic syndromes despite use of immunosuppressive therapies.
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-043 - A Phase 1b Study of Erlotinib and Momelotinib for TKI-Naïve EGFR-Mutated Metastatic Non-Small Cell Lung Cancer (ID 9551)
09:30 - 09:30 | Presenting Author(s): Sukhmani Kaur Padda
- Abstract
Background:
In this study (NCT02206763), momelotinib, an inhibitor of Janus kinases 1 and 2, was administered in combination with erlotinib, a tyrosine kinase inhibitor (TKI) in patients with TKI-naïve epidermal growth factor receptor (EGFR)-mutated metastatic non-small cell lung cancer (NSCLC), to determine the maximum tolerated dose and safety of momelotinib in combination with erlotinib. As previously reported, dose limiting toxicities (DLTs) of grade 3 diarrhea (n=1) and grade 4 neutropenia (n=1) without fever were seen at dose level (DL) 2B and trial enrollment was halted. Here, we report the final results.
Method:
Patients received oral erlotinib 150 mg QD (including 11-31 day run-in). Momelotinib was administered orally in a standard 3+3 dose-escalation design: DL1, momelotinib 100 mg QD; DL2A, 200 mg QD; and DL2B, 100 mg BID. DLTs were evaluated in the first 28 days. Plasma samples were collected for PK/PD analyses.
Result:
Eleven patients enrolled: 3 in DL1, 3 in DL2A, and 5 in DL2B. The median duration of exposure to momelotinib was 40 weeks (range 2.4-63.1) and median number of cycles was 10 (range 0.6-15.8). Treatment was discontinued for progressive disease (n=7), adverse event (n=3), and patient decision (n=1). The objective response rate was 54.5% (90% CI: 27.1%–80.0%) and all responses (n=6) were partial responses; 4 patients had stable disease and 1 patient had progressive disease. The median duration of response was 7.1 (90% CI: 4.4–9.6) months. The median progression-free survival was 9.2 (90% CI: 6.2–12.4) months. The estimated median overall survival was not reached. The most common treatment-emergent adverse events (TEAEs) were decreased appetite, dry skin, and fatigue (7 patients each) and diarrhea (6 patients). In addition to the patient with grade 4 neutropenia (DLT), decreased neutrophil count was recorded in 4 additional patients (grade 1-2 [n=3], grade 3 [n=1]); median time to first neutrophil abnormality was 0.5 (range 0.5–3.7) months. Momelotinib-related TEAEs of interest (one patient each) included grade 1 sensory peripheral neuropathy, grade 1 paresthesia, and reactivation of hepatitis B. There was one momelotinib-related serious adverse event, grade 3 pneumonitis. There was no PK interaction between momelotinib and erlotinib.
Conclusion:
The combination of momelotinib and erlotinib had more toxicity than expected at DL2B. Neutropenia was common. Although the small number of patients in this phase 1 study limits our ability to make a definitive conclusion regarding efficacy, the response rate and progression-free survival was similar to previous reports with erlotinib alone.
