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Despite the critical roles played by IFN-γ+ CD4 Th1 response in tumor immunity, the translation of their potential in clinic remains challenging. Here, we evaluate the clinical significance of circulating anti-tumor CD4 Th1 response in non-small cell lung cancer (NSCLC) patients. 170 naïve-treatment patients were enrolled in this immune monitoring study. The antitumor adaptive Th1 response was assessed by IFN-γ ELISPOT assay in blood lymphocytes using a mixture of eight highly promiscuous and Th1-polarized HLA class II-restricted epitopes from telomerase (TERT). The presence of anti-TERT Th1 response was detected in 59/170 patients (35%). We found an opposite link between anti-TERT Th1 and hyper exhausted T cells co-expressing PD-1+ and TIM-3+ in NSCLC patients. In contrast to hyper exhausted CD8 T cells, the presence of anti-TERT Th1 response was associated with a low rate of hyper exhausted CD4 T cells. We showed that NSCLC stage dissemination is associated with a decrease of anti-TERT Th1 response but an increase of circulating hyper exhausted PD-1+/TIM-3+ CD4 T cells. Notably, anti-telomerase Th1 response and hyper exhausted CD4 T-cells displayed opposite prognosis value in NSCLC. While high level of anti-TERT Th1 cells play a protective role, hyper-exhausted PD-1+TIM-3+ CD4 T cells negatively affect patients’ survival. By using these two circulating immune factors, we stratified patients in distinct prognostic group. Patients with anti-TERT Th1high/CD4 PD-1 TIM-3low immune profile had better overall survival than anti-TERT Th1low/CD4 PD-1 TIM-3high group (median OS : not reached versus 4 months respectively p Citation Format: Caroline Laheurte, Magalie Dosset, Dewi Vernerey, Elodie Lauret Marie Joseph, Laura Boullerot, Vincent Kaulec, Marion Jacquin, Laurie Cuche, Guillaume Eberst, Pascale Jacoulet, Virginie Westeel, Olivier Adotevi. Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 575.

Cumulative evidence supports that CD4(+) Th1 cells play a key role in antitumor immunity. We previously reported the presence of spontaneous HLA-DR-restricted CD4(+) Th1 responses against telomerase reverse transcriptase (TERT) in various cancers by using promiscuous HLA-DR epitopes. Here, we described novel highly immunogenic HLA-DP4-binding epitopes from TERT named TERT541-555, TERT573-587, TERT613-627 and TERT911-925 and addressed the question about the immunoprevalence and magnitude of the naturally occurring antitumor CD4(+) T cell responses restricted by HLA-DP4 or HLA-DR, the two most common HLA class II. Direct comparative study of spontaneous anti-TERT CD4(+) T cell responses in a cohort of 87 lung cancer patients showed that HLA-DP4 and HLA-DR sustained specific Th1 responses in 10.1% and 25.2% of cancer patients respectively (p = 0.01). The magnitude of the HLA-DR-restricted responses was two to three times significantly higher than HLA-DP one (p = 0.005). Similar results were found in other cancers such as melanoma, breast cancer, renal cell carcinoma and colon cancer. Thus, our results describe for the first time in a large cohort of cancer patients a high immunoprevalence of HLA-DR-restricted spontaneous anti-TERT Th1 immunity compared to HLA-DP restriction. These results provide a new tool for comprehensive monitoring of antitumor CD4(+) Th1 response in various cancers.

This study reports the results of 120 patients with inoperable non-small cell lung cancer treated with Navelbine at a dose of 25-30 mg/m2/week in a single-drug chemotherapy regimen. Surgery was contraindicated due to staging or to concomitant morbidity. Twenty patients achieved survival greater than or equal to 18 months, and one patient obtained exceptional survival of more than 120 months. The mean dose intensity of Navelbine in long-term survivors was 21.61 mg/m2/week. Objective response to Navelbine was found by multivariate analysis to be a prognostic factor for survival beyond 18 months. Weight loss of more than 5 kg of corporal weight was an unfavorable prognostic factor in patients with metastatic disease.

Summary Background The aim of this study was to analyze SCLC patients beyond 30 months, particularly their outcome, their way of life, and factors which could influence relapses, second-primary cancers and death. Patients and methods Between January 1986 and May 1995, 263 SCLC patients who survived longer than 30 months were included from 52 French institutions. The analysis was performed on the 155 cases confirmed by a pathologic review. Results Physical, mental and psychological states were considered as normal at 30 months in respectively 70.3%, 87.7% and 67.7% of patients, not influenced by prophylactic cranial irradiation, number of chemotherapy cycles, CCNU or cisplatin. Therapeutic sequelae were neurological impairment (13%), pulmonary fibrosis (18%) and cardiac disorders (11%) at 30 months. Return to work was possible for 40% of patients in the first two years following diagnosis. Among 43 relapsing patients, 33 benefited from a second-line treatment. Their median survival was 12 months since retreatment, and seven patients have survived again longer than 30 months. Age > 60 at the time of diagnosis was found as an independent factor increasing the risk of relapse beyond 30 months (OR = 2.46, IC 95% (1.16–5.26), P = 0.01). The risk of relapse became less than 10% beyond five years. Twenty patients (13%) developed a second primary cancer in a mean time of 58.6 months. The risk of second primary cancer was increased by a number of chemotherapy cycles > 6 (OR = 3.25, IC 95% (1.08–9.8) P = 0.02) and by an age > 60 (OR = 2.92, IC 95% (1.07–7.97), P = 0.03). Five- and 10-year survival rates were respectively 68% and 44%. In these patients having reached a 30-month survival, three independent factors were predictive of a survival longer than five years: age ≤60 at the time of diagnosis (OR = 2.85, IC 95% (1.23–6.6), P = 0.01), chest radiotherapy (OR = 3.1, IC 95% (1.28–7.69), P – 0.006) and absence of relapse (OR = 4.5, IC 95% (1.75–12.5), P – 0.002). This study suggests that: 1) therapeutic sequelae are rather mild, allowing return to work in 40% of patients; 2) relapsing 30-month survivors can benefit from second-line treatment; 3) SCLC cure can be achieved with a 10-year follow-up.

Summary Purpose The purpose of the study was to assess the possible benefit of the combination vinorelbine (NVB)-cisplatin (DDP) in comparison with NVB alone in advanced non- small cell lung cancer (NSCLC), not treated previously. It also involved confirmation of the efficacy of vinorelbine as monotherapy. Patients and methods In this phase 111 trial, 231 eligible patients were stratified by centre and randomized to receive either NVB alone, 30 mg/m2/week or the combination of NVB 30 mg/m2/week and DDP 80 mg/m2/3 weeks. Patients were to be treated for a minimum of 6 weeks, with the first response assessment performed 9 weeks after the beginning of treatment. Results The two groups differed in terms of objective response rates (16% and 43%, respectively, p = 0.0001) and median time to progression (10 weeks and 20 weeks, p = 0.0001). However, the difference was not significant for median survival time (32 weeks, 33 weeks, p = 0.48). The addition of DDP resulted in an increase in toxicity, in particular renal, hematologic, neurologic and emetic. This toxicity led to treatment discontinuation in 8% and 21% of patients, respectively. Respectively 3% and 13% of patients stopped treatment early during objective response (toxicity or refusal). Conclusions The NVB-DDP combination increased objective response rates and time to progression in comparison with NVB alone, but did not influence the survival of patients. The activity of NVB in the treatment of advanced NSCLC was confirmed.

International audience; BACKGROUND: The interest of first- and second-line treatments in non-small cell lung cancer (NSCLC) has been demonstrated by successive randomized trials. Improvements in lung cancer care have routinely allowed a significant proportion of patients to be considered for third-line treatment. METHODS: A retrospective analysis was performed, including all consecutive patients with advanced NSCLC, who received at least three lines of systemic antineoplastic treatment at our institution. RESULTS: From a population of 613 patients treated with first-line treatment, a total of 173 patients received third-line treatment (cytotoxic chemotherapy in 131 patients; epidermal growth factor (EGFR) tyrosine kinase inhibitors in 42 patients). Only 13 patients (8%) received less than 75% of the theoretical dose intensity; 22 patients (13%) presented with severe toxicities. Symptom relief and performance status (PS) improvement were observed in 121 (92% of the 131 patients with symptoms) and 90 patients (52%), respectively. Using multivariate analysis, survival after third-line treatment was significantly increased in patients younger than 70 years-old (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.53-0.99, p = 0.047), who smoked less than 10 pack-years (HR = 0.82, 95% CI: 0.57-0.93, p = 0.036), with no cancer-related symptoms (HR = 0.75, 95% CI: 0.61-0.92, p = 0.007), a weight loss inferior to 5 kg since the beginning of second-line (HR = 0.63, 95% CI: 0.52-0.75, p = 0.013), a PS 0 to 1 (HR = 0.81, 95% CI: 0.76-0.86, p = 0.008), and no extrathoracic tumor spread at initiation of third-line treatment (HR = 0.67, 95% CI: 0.47-0.94, p = 0.042). Disease control after both first- and second-line treatments was the strongest predictor of prolonged survival after third-line treatment (HR = 0.47, 95% CI: 0.33-0.67, p = 0.001). CONCLUSIONS: Patients with advanced NSCLC may benefit from third-line treatment. The best candidates can be identified using standard prognostic factors, such as PS, and disease control after first- and second-line treatments.

Summary Background Although the average age of lung cancer patients is increasing, many elderly patients remain undertreated, mainly because of the fear of higher treatment toxicity in this category of patients. We conducted a study to evaluate the efficacy and tolerability of a combination therapy with carboplatin (C) and etoposide phosphate (EP) in elderly patients with Small-Cell Lung Cancer (SCLC). Patients and methods Previously untreated patients older than 70 years with stage IIIB/IV SCLC received a combination of EP (100 mg/m2 D1, D2, D3) and C (Dl, dose calculated according to the Calvert formula). Response rate, survival and toxicity were assessed. Results Thirty-eight patients (mean age 76 years, range 70–88 years) received a total of 162 cycles. Eighteen patients (47%) received the six scheduled cycles. Thirty patients were evaluable for efficacy (2 CR and 20 PR). The median survival was 237 days and the one-year probability of survival was 26%. The most common adverse effect was transient grade 3 or 4 neutropenia, observed during 57% of evaluable cycles, while five episodes of febrile neutropenia also occurred, with one fatal (bactaeriemia). It is noteworthy that no renal or liver toxicity was observed, and no mucitis was noted. Unfortunately, a relatively high proportion of patients died shortly after the start of the study. Although most deaths seemed unrelated to the treatment, the possibility of its exacerbatory effect on comorbidities, especially cardiovascular, cannot be excluded. Conclusion The two-drug regimen of carboplatin and etoposide phosphate is feasible in most elderly patients with an acceptable toxicity, and the overall results suggest that patients even older than 70 years may benefit from full treatment. Therefore, consideration should be given to offering active treatment to most patients with SCLC, regardless of age but with special attention paid to comorbidities.

The aim of this study was to analyze SCLC patients beyond 30 months, particularly their outcome, their way of life, and factors which could influence relapses, second-primary cancers and death.Between January 1986 and May 1995, 263 SCLC patients who survived longer than 30 months were included from 52 French institutions. The analysis was performed on the 155 cases confirmed by a pathologic review.Physical, mental and psychological states were considered as normal at 30 months in respectively 70.3%, 87.7% and 67.7% of patients, not influenced by prophylactic cranial irradiation, number of chemotherapy cycles, CCNU or cisplatin. Therapeutic sequelae were neurological impairment (13%), pulmonary fibrosis (18%) and cardiac disorders (11%) at 30 months. Return to work was possible for 40% of patients in the first two years following diagnosis. Among 43 relapsing patients, 33 benefited from a second-line treatment. Their median survival was 12 months since retreatment, and seven patients have survived again longer than 30 months. Age60 at the time of diagnosis was found as an independent factor increasing the risk of relapse beyond 30 months (OR = 2.46, IC 95% (1.16-5.26), P = 0.01). The risk of relapse became less than 10% beyond five years. Twenty patients (13%) developed a second primary cancer in a mean time of 58.6 months. The risk of second primary cancer was increased by a number of chemotherapy cycles6 (OR = 3.25, IC 95% (1.08-9.8) P = 0.02) and by an age60 (OR = 2.92, IC 95% (1.07-7.97), P = 0.03). Five- and 10-year survival rates were respectively 68% and 44%. In these patients having reached a 30-month survival, three independent factors were predictive of a survival longer than five years: ageor = 60 at the time of diagnosis (OR = 2.85, IC 95% (1.23-6.6), P = 0.01), chest radiotherapy (OR = 3.1, IC 95% (1.28-7.69), P = 0.006) and absence of relapse (OR = 4.5, IC 95% (1.75-12.5), P = 0.002). This study suggests that: 1) therapeutic sequelae are rather mild, allowing return to work in 40% of patients; 2) relapsing 30-month survivors can benefit from second-line treatment; 3) SCLC cure can be achieved with a 10-year follow-up.