Background: Despite vaccination, COVID-19 could still cause severe disease in immunocompromised patients (pts). While subsequent vaccine doses increase immune response in the general population, few data concerning cancer pts under systemic treatment are reported. Methods: This study will be conducted on blood samples from 1000 pts admitted to Reggio Emilia AUSL-IRCCS Cancer Center and undergoing systemic therapies who received ≥ 2 vaccine doses. The samples will be analyzed at Clinical Microbiology and Chemistry Laboratories of Reggio Emilia AUSL-IRCCS. We will perform antibody IgM-IgG serology by means of COVID-19 VIRCLIA® Monotest and anti-spike antibodies evaluation using LIAISON® SARS CoV-2 Trimerics IgG. We will also investigate cell immune response (B and T lymphocyte counts) and analyze specific lymphocyte subsets on the first 200 pts treated with chemo- (CT) or immunotherapy (IO). Then, we will evaluate the T-cell response on the first 50 pts and those with an inadequate anti-spike serologic response through the T-SPOT.COVID test. Statistical analyses will be conducted by the Clinical Studies and Statistical Unit Staff. Results: Here, we report preliminary data on the first 240 pts enrolled and treated with CT (55.4%), IO (26.3%), or other therapies (18.3%). Most of the pts were male (58%), had metastatic cancer (82%), and no previous COVID-19 infection (60%). 84% of pts were affected by gastrointestinal, lung, urogenital and breast cancer. We stratified pts in three groups according to the time from the last vaccine dose (0-6/6-12/ > 12 months). We showed no significant decrease in cellular and humoral immune response over time from the last vaccine dose, independent of the specific treatment received, also if CT (Table 1). Furthermore, clinical characteristics as gender, treatment, and primary tumor site appear not to influence immune response, even if a trend to a higher response in pts previously affected by COVID-19 has been observed. The T-SPOT.COVID test performed on the first 27 pts showed that 19% had no T-cell activation, even with good IgG response. Conclusions: This feasible and cost-effective study has a potential impact on public health. Although these are preliminary data, the immune response to COVID-19 vaccines remains good after 12 months from the last dose administered in cancer pts. The enrollment is ongoing, and we could provide relevant information on the influence of clinical factors on the immune response and identify specific subgroups that could benefit from different vaccine approaches.