Aim: Currently, malignant diseases represent a health issue worldwide. Among these, lung cancer is of growing importance, due to its high incidence and mortality. Chemotherapy, one of the most frequently used treatments, has shown its ability to induce accelerated immunosenescence in classic and as well non-classic lymphocyte compartments, being less described in the latter. The immune restoration strategies have demonstrated their ability to reverse immunosenescence and exhaustion markers in conventional lymphocyte subpopulations after chemotherapy. However, the possible immunorestorative effect on non-classical lymphocytes has not been widely reported. The aim of this study was to evaluate the effect of chemotherapy and the administration of a thymic polypeptide factor on non-classical lymphocyte populations in patients with advanced lung cancer. Methods: Eighteen patients with advanced lung cancer, were evaluated at baseline before and after platinum-based chemotherapy (4–6 cycles). All patients could complete treatment with a thymic polypeptide factor [Biomodulina T (BT)] at the end of chemotherapy. Blood from patients was collected by venipuncture in heparinized tubes before and after chemotherapy and at the end of BT treatment to analyze the frequencies of non-classical immune subpopulations by flow cytometry. Results: Natural killer (NK), natural killer T cells (NKT), and double-positive T lymphocyte (DPT) proportions reached normal values in patients diagnosed with advanced lung cancer before receiving cytotoxic treatment. Chemotherapy did not induce modifications in the total percent of NK, NKT, and DPT populations in these patients. However, the administration of BT decreased DPTs and NK cells expressing the cluster of differentiation (CD)57 molecule, which is considered a marker of immunosenescence. Conclusions: These results suggest a lower influence of platinum-based chemotherapy on non-classical lymphocytes and the potential to generate a reconstitution of lymphocyte subpopulations in patients with advanced lung cancer by using the thymic factor BT, which reveals a new possibility for improving the response to cancer immunotherapies [Cuban Public Registry of Clinical Trial (RPCEC, https://rpcec.sld.cu/en/trials/RPCEC00000358-En) identifier: RPCEC00000358].

Background: EGFR has been suggested to contribute to COPD development and progression. Excessive ligand activation of the receptor leads to epithelial hyperproliferation and increased production of mucus, together with alterations in the primary cilia. The present study was designed to evaluate the safety and effect of depleting EGF in moderate-to-severe COPD patients, with an EGF-based vaccine. Patients and methods: A phase I trial was conducted in subjects with moderate or severe COPD. The anti-EGF vaccine schedule consisted of 4 biweekly doses followed by 4 monthly boosters. The primary endpoint was the evaluation of the safety and immunogenicity of the vaccine, together with the change in FEV1 and physical function at week 24. Results: Twenty-six patients with moderate or severe COPD were included in the trial. The vaccine was well tolerated and no serious related adverse events were reported. Ninety percent of the individuals developed a protective antibody response. The specific anti-EGF antibodies had high avidity and were able to inhibit EGFR phosphorylation. At the end of vaccination, serum EGF became undetectable. At week 24, there was a clinically significant improvement in lung function, with a mean change in trough FEV1 of 106 mL. Patients also increased their physical functioning. Conclusions: The EGF-based vaccine was immunogenic and provoked an EGF exhaustion in patients with moderate-to-severe COPD. Depleting EGF might result in a meaningful increase in FEV1, with good tolerability. The current results provide new avenues to treat chronic inflammatory lung diseases associated with EGFR aberrant signaling.

Background: CD6 is a promising target in cancer immunotherapy, with preclinical evidence supporting its role in modulating immune responses. This warrants further investigation into current CD6-targeting treatments, which could lead to new anti-tumor therapies. However, the clinical effects of targeting CD6 in solid tumors remain unexplored. Methods: This proof-of-concept study is the first in-human evaluation of the safety and early effectiveness of anti-CD6 monoclonal antibody itolizumab in patients with advanced, highly heterogeneous solid tumors. Treatment had two phases: induction and maintenance. In induction, group A received 100 mg weekly for nine doses; group B received 200 mg biweekly for five doses. After completing induction, patients moved to maintenance 21 days later, receiving 100 mg every 21 days for up to six doses. The primary endpoint was safety; secondary objectives included disease control, survival, and exploratory molecular mechanisms and blood biomarkers. Results: Itolizumab demonstrated a favorable safety profile, with no safety-related treatment discontinuations, no related serious adverse events, and no unexpected toxicities. In this heavily treated, non-biomarker-selected population, disease control was achieved in 25% in group A and 20% in group B, and the 1-year survival rate was 26% in group A and 15% in group B. Mechanistically, ex vivo analysis demonstrated that itolizumab downregulates CD6, increasing soluble CD6 levels and promoting a cytotoxic phenotype on CD8 and NK cells. Additionally, patient-derived peripheral blood mononuclear cells demonstrated boosted in vitro killing capacity specifically against CD318+ cancer cells. The antibody also modulates PD-1 expression in peripheral lymphocytes, promoting NK cell activity while maintaining inhibitory signals on CD8+ T cells and decreasing T helper overactivation. These findings support the dual role of itolizumab, enhancing anti-tumor responses while preventing autoimmune-like effects by reducing off-target inflammation and avoiding immune-related adverse effects associated with immune checkpoint therapies. Conclusions: Overall, these findings support further development of itolizumab as a rational immunomodulatory strategy with a favorable safety profile for advanced solid tumors, particularly in CD318-expressing tumors and as part of rational combination regimens. Trial registration number: RPCEC00000444.