https://doi.org/10.1038/s41586-021-03363-z Received: 19 October 2020 Accepted: 16 February 2021 Published online: 24 March 2021 Open access Check for updates A list of affiliations appears at the end of the paper. 464 | Nature | Vol 592 | 15 April 2021 ArticleTwo patients (ID19, ID21) were enrolled but could not be evaluated for immunogenicity testing and were therefore excluded from the immu - nogenicity analysis. Thirty out of the 32 patients in the SDS (93.8%) and 28 of the 30 patients in the immunogenicity dataset (IDS; 93.3%) reached the end of treatment (EOT). The maximum treatment dura - tion was 23 weeks. The median follow-up time (as of June 2020) was 46.9 months (95% confidence interval (CI): 45.2–49.2 months) for the SDS and 47.1 (45.2–49.2) months for the IDS. IDH1-vac is safe and immunogenic The SDS comprised 249 vaccines administered to 32 patients. Twenty-nine out of 32 patients in the SDS (90.6%) and 27 out of 30 patients in the IDS (90.0%) received all 8 vaccinations; one patient received 7, one received 6, and one received 4 vaccinations. The duration of treatment in the SDS ranged from 44 to 162 days (median, 155 days) and the duration of observation ranged from 153 to 484 days (median 376 days). Quality control demonstrated that all vaccines contained 300 ± 30 μg peptide, and were sterile and free from endo - toxins. No regime-limiting toxicity (RL T) was observed. The overall serum cytokine profile was indicative of an adverse cytokine release in response to IDH1-vac (Extended Data Fig. 2). Twenty-nine of the 32 patients (90.6%) had treatment-related adverse events, none of which was severe. One patient (3.1%) had treatment-related serious adverse events, and one patient (3.1%) temporarily discontinued the study drug due to treatment-related adverse events (Supple - mentary Tables 4, 5). Twenty-one (65.6%; 95% CI 46.81–81.43%) and 15 (46.9%; 95% CI 29.09–65.26%) of the adverse events classified as possibly related to IDH1-vac were local administration site condi - tions (injection site induration or erythema, respectively). Of the 30 patients in the IDS, 28 (93.3%; 95% CI 77.93–99.18%) displayed IDH1-vac-induced immune responses (Fig. 2a, b ). IDH1-vac-induced T cell immune responses were observed in 26 of 30 patients and B cell immune responses in 28 of 30 patients across multiple human leukocyte antigen (HLA) alleles; these responses did not correlate with in vitro HLA affinities of the IDH1(R132H) peptide (Extended Data Fig. 3, Supplementary Table 6). Two patients (6.7%) developed neither T cell nor B cell immune responses (Extended Data Fig. 3). To incorporate the duration and level of IDH1-vac-induced T cell immune responses specifically to IDH1(R132H), we established an explorative mutation-specificity score (MSS; Supplementary Table 7, Extended Data Figs. 4, 5). Flow cytometric effector sub-phenotyping of periph - eral IDH1-vac-induced T cells from available patient samples with high MSSs showed predominant tumour necrosis factor (TNF), interferon-γ (IFNγ), and interleukin-17 (IL-17) cytokine production by T helper (TH) cells upon in vitro re-stimulation with IDH1(R132H), which indicates the involvement of TH1 and TH17 subtypes of TH cells (Fig. 2c, Extended Data Fig. 4). Neither IL-10 production by regulatory T cells nor TNF or IFNγ production by cytotoxic T cells was observed (Fig. 2c). Moreo - ver, the MSS was associated with intratumoral IDH1(R132H) antigen presentation in pre-treatment tumour tissue, as assessed by an in situ MHCII–IDH1(R132H) proximity ligation assay (PLA)5 (Fig. 2d, Extended Data Fig.