BackgroundAutologous cell therapies with an engineered T-cell receptor targeting MAGE-A4 have shown responses in patients with synovial sarcoma1 with additional responses in myxoid/round cell liposarcoma (MRCLS), head and neck, lung, esophagogastric junction, and melanoma cancers.2 3 Low-dose radiation may control tumor growth locally and modulate stroma of solid tumors,4 potentially facilitating T-cell infiltration into tumors and antitumor activity.MethodsSub-study designed to assess safety, tolerability, and efficacy in up to 10 patients with low-dose radiation in combination with lymphodepleting chemotherapy, followed by afami-cel (an autologous TCR cell T-cell therapy targeting MAGE-A4). Eligible patients are HLA-A*02^+ with MAGE-A4 expressing tumors including urothelial, melanoma, head and neck, ovarian, non-small cell lung, esophageal, gastric, synovial sarcoma, and MRCLS cancers. Patients receive afami-cel by infusion following low-dose radiation and lymphodepleting chemotherapy. Radiation was 4.2–7 Gy per lesion or isocenter (maximum of 5). Lymphodepleting regimen was IV fludarabine 30 mg/m^2/day for 4 days (−7 to −4) and cyclophosphamide 600 mg/m^2/day for 3 days (−7 to −5). Afami-cel doses ranged from 1.2 x 10^9 to 10 x 10^9 transduced cells. Pts receive afami-cel infusion on Day 1.ResultsAs of Dec 27, 2020, a total of 8 patients, including 4 patients (1 male) with melanoma (2), HNSCC (1), or ovarian (1) cancers received low-dose radiation and afami-cel. Most frequently reported AEs (4/4 pts) were leukopenia/decreased white blood cell count, lymphopenia/decreased lymphocyte count, and neutropenia/decreased neutrophil count; all of which were related to the lymphodepletion regimen. The most commonly (>1 patient) reported AEs considered related to T-cell infusion were cytokine release syndrome (2/4 pts) and fatigue (2/4 pts). Two patients had a total of 5 SAEs: adrenal insufficiency, hyperglycemia, neurotoxicity, pneumonia aspiration, and pneumothorax. The only SAE considered to be related to treatment was Grade 3 neurotoxicity. Best overall responses per RECIST 1.1: 1 partial response (melanoma, −42% in target lesions), 2 stable diseases (ovarian cancer, −23%; HNSCC, no change), and 1 patient did not have post-baseline scans yet. Translational analyses showed peripheral persistence and serum cytokine response profiles consistent with that of afami-cel monotherapy, whilst a relatively greater T cell infiltration in tumor biopsies was evident.ConclusionsAfami-cel with low-dose radiation has had an acceptable safety profile. Most AEs were consistent with those typically experienced by cancer patients undergoing lymphodepletion cytotoxic chemotherapy and cellular therapy. Infused T-cells were observed in tumor biopsies at high frequency, and one patient exhibited a clinical partial response.Trial RegistrationNCT03132922ReferencesVan Tine BA, et al. CTOS 2020.Hong DS, et al. ASCO 2020.Hong DS, et al. SITC 2020.De Selm C, et al. Mol Ther 2018;26(11):2542–2552.
Purpose/Objective(s): Lobectomy followed by adjuvant chemotherapy is the standard of care for patients with clinically T1-T2N1 non-small cell lung cancer (NSCLC). However, the optimal treatment of patients who cannot undergo or refuse to undergo surgical resection is controversial. Currently, NCCN guidelines recommend concurrent chemoradiation; however, limited evidence exists to substantiate this recommendation for this particular patient population. Many groups advocate for radiation alone with standard or hypofractionated approaches. We hypothesized that concurrent chemoradiation would be associated with longer overall survival (OS) compared to hypofractionated or conventionally fractionated radiation. Materials/Methods: We queried the National Cancer Database (NCDB) for patients with cT1-T2N1M0 NSCLC treated non-surgically with definitive radiation or concurrent chemoradiation between 2004 and 2016. We further restricted our cohort to patients receiving RT doses with an EQD 2 ≥ 58.4 Gy and > 5 fractions. Patients were divided into four treatment groups: standard fractionated radiation (SFRT), hypofractionated radiation (HFRT), standard fractionated chemoradiation (SFRT+CT), and hypofractionated chemoradiation (HFRT+CT). Chemoradiation was defined as chemotherapy and radiation with start dates within 30 days. To address confounding by indication, inverse probability of treatment weights (IPTW) were constructed regressing sociodemographic, clinical, and facility characteristics on treatment group in a multinomial regression model. Weighted Cox proportional hazard regression models were then used to evaluate the relative hazard of death with SFRT set as the referent treatment group. Results: A total of 2,534 patients met inclusion criteria and of these 2,200 patients (57,462.83 person-months) had complete data for all confounders and were included in the analytic sample. Of the 2,200 patients 26.6% received SFRT, 7% received HFRT, 62.1% received SFRT+CT, and 4.2% received HFRT+CT. The median EQD 2 (IQR) were:
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