Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMβ2), and plays an important role in recruitment and biological functions of these cells, and is a validated therapeutic target. Here, we describe our pre-clinical studies targeting CD11b in the context of lung cancer, using pharmacologic and genetic approaches that work via positive allosteric modulation of CD11b function. GB1275 is a novel small molecule modulator of CD11b that is currently in Phase 1/2 clinical development. We assess GB1275 treatment effects on tumor growth and immune infiltrates in the murine Lewis Lung Carcinoma (LLC) syngeneic tumor model. Additionally, as an orthogonal approach to determine mechanisms of action, we utilize our recently developed novel CD11b knock-in (KI) mouse that constitutively expresses CD11b containing an activating isoleucine to glycine substitution at residue 332 in the ligand binding CD11b A-domain (I332G) that acts as a positive allosteric modulator of CD11b activity. We report that pharmacologic modulation of CD11b with GB1275 significantly reduces LLC tumor growth. CD11b KI mice similarly show significant reduction in both the size and rate of LLC tumor growth, as compared to WT mice, mimicking our observed treatment effects with GB1275. Tumor profiling revealed a significant reduction in TAM infiltration in GB1275-treated and in CD11b KI mice, increase in the ratio of M1/M2-like TAMs, and concomitant increase in cytotoxic T cells. The profiling also showed a significant decrease in CCL2 levels and a concomitant reduction in Ly6C^hi monocytes in circulation in both groups. These findings suggest that positive allosteric modulation of CD11b reduces TAM density and reprograms them to enhance the adaptive immune response and is a novel therapeutic strategy against lung cancer.

Https://doi.org/10.18632/oncotarget.28202 Alexander W. Pohlman, Hita Moudgalya, Lia Jordano, Gabriela C. Lobato, David Gerard, Michael J. Liptay, Christopher W. Seder, Jeffrey A. Borgia

Background/Objectives: Total thymectomy is currently the gold standard operation for treating thymoma. However, recent studies have suggested the potential health consequences of thymus removal in adults, including possible increased autoimmune disease and all-cause mortality. In this context, we assess oncologic outcomes following total vs. partial thymectomy for early-stage thymoma. Methods: We identified patients diagnosed with WHO types A–B3 thymoma between 2010–2021 from a national hospital-based dataset. We excluded patients with stage II or higher disease, open resections and perioperative chemo-/radiation therapy. We stratified patients into total and partial thymectomy cohorts. We used propensity score matching to minimize confounding, Kaplan–Meier analysis to estimate survival, and Cox proportional hazards to identify associations. Results: Of 1598 patients with early-stage thymoma, 495 (31.0%) underwent partial and 1103 (69.0%) total thymectomy. Patients undergoing partial thymectomy were similar in sex (female 53.7% vs. 53.4%; p = 0.914), race (white 74.5% vs. 74.0%; p = 0.921), comorbidities (0 in 77.0% vs. 75.5%; p = 0.742), and tumor size (48.7 mm vs. 50.4 mm; p = 0.455) compared to total thymectomy. There were no differences in 30-day (0.8% vs. 0.6%, p = 0.747) or 90-day mortality (0.8% vs. 0.8%, p > 0.999), which persisted after matching. Moreover, 10-year survival was similar in both unmatched (p = 0.471) and matched cohorts (p = 0.828). Partial thymectomy was not independently associated with survival (aHR = 1.00, p = 0.976). Conclusions: In patients with early-stage thymoma, partial and total thymectomy were associated with similar short- and long-term outcomes. In light of recent attention to the role of the thymus gland, the results add important insights to shared decision-making discussions.

Background: Minimally invasive video-assisted thoracoscopic surgery (VATS) for tracheal cancer is gaining popularity. However, data are limited to single-center reports and short-term outcomes. In this context, we aim to compare short and long-term oncologic outcomes of VATS versus open tracheal cancer resection at the national level. Methods: We used a national dataset to isolate primary tracheal cancers diagnosed between 2010–2021. Patients were stratified by operative approach into open and VATS resection groups. Cox analysis was used to estimate proportional effects of covariates in unmatched cohorts. We then used propensity score matching to minimize confounding bias from covariates. Kaplan-Meier survival analyses were used to estimate 5-year survival. Results: Of 331 patients undergoing tracheal cancer resection, 147 (44.4%) were started VATS with 5 (3.4%) converting to open. Patients undergoing VATS tracheal resection were similar in age (62.4±14.5 vs. 59.9±14.2 years; P=0.12), race (White =81.0% vs. 84.8%; P=0.32) and Charlson-Deyo comorbidity (index =0, 59.2% vs. 68.5%; P=0.19), but were more likely to be male (57.8% vs. 46.2%; P=0.04) and have positive margins (58.1% vs. 41.0%; P=0.006) compared to open resection. Post-operative length of stay was shorter with VATS (median 2.5 vs. 7.0 days; P<0.001), but this came at the expense of higher rates of positive margins [adjusted odds ratio (aOR) =2.15, P=0.02] and worse median survival (74 vs. 106 months; P<0.001), which persisted after matching (79 vs. 100 months; P=0.01). Conclusions: In this national observational study, we found that the short-term benefits of thoracoscopic tracheal resection come at the expense of increased positive margins and worse survival. Adoption of this approach for tracheal cancer should be met with caution.

Osimertinib is now approved as adjuvant therapy for stage IB to III NSCLC with EGFR mutations. Nevertheless, this treatment is lengthy and expensive. Its cost-effectiveness profile as monotherapy versus combination with chemotherapy is unknown. In this context, we investigate the cost-effectiveness of adjuvant osimertinib with and without chemotherapy for NSCLC. A set of Markov models was established to predict the cost-effectiveness of these different regimens. Data were sourced from the ADAURA trial’s publications and protocols. Health outcomes were quantified as quality-adjusted life-years (QALYs). Costs and incremental cost-effectiveness ratios (ICERs) were estimated in U.S. dollars (USD) and USD per QALY, respectively. Deterministic and probabilistic sensitivity analyses were performed. Data from the Surveillance, Epidemiology, and End Results Program were used to predict additional costs to the U.S. health care system. Compared with treatment with chemotherapy alone, treatment with osimertinib plus chemotherapy yielded 5.86 QALYs with incremental costs of $414,607.69 (ICER = $380,347.85 per QALY). Treatment with osimertinib alone yielded 6.63 QALYs with an incremental cost of $402,224.32 (ICER = $213,447.59 per QALY). Osimertinib is only likely to be cost-effective if the willingness-to-pay threshold per QALY is $200,000 or more. The price of osimertinib had the strongest influence on cost-effectiveness. On the basis of Surveillance, Epidemiology, and End Results Program data, these practices may cost the U.S. health care system an additional 8.9 billion USD/year. Adjuvant osimertinib alone is more cost-effective than combination therapy, but only if the willingness-to-pay is high. A reduction in the price of osimertinib would improve its cost-effectiveness profile.