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Background: CV8102, a toll-like receptor 7/8 and RIG I agonist, has demonstrated antitumor immune responses in preclinical studies. We investigated intratumoral (IT) administration of CV8102 in patients with anti-programmed cell death protein-1 (PD-1) therapy-naïve or anti-PD-1 therapy-refractory cutaneous melanoma (cMEL) and in patients with advanced cutaneous squamous cell carcinoma, head and neck squamous cell carcinoma and adenoid cystic carcinoma., Methods: This open-label, cohort-based, phase I dose escalation study aimed to establish the maximum tolerated dose (MTD), recommended dose (RD), safety and preliminary efficacy of CV8102 as monotherapy or in combination with a PD-1 inhibitor. The preliminary efficacy of the RD was assessed in patients with cMEL in the expansion cohorts., Results: Between September 2017 and October 2022, 98 patients were enrolled in monotherapy and combination therapy dose escalation and dose expansion cohorts. Two patients in the CV8102 monotherapy dose escalation cohort experienced relevant toxicities at the 900 µg dose level. One patient had Grade 3 aspartate transaminase/alanine aminotransferase elevation which met dose-limiting toxicity (DLT) criteria. Another patient experienced Grade 3 immune-mediated pneumonitis. No DLTs occurred in the combination therapy dose escalation cohort. The MTD was not formally reached and the RD for expansion was 600 µg. Common treatment-emergent adverse events were fever (57%), chills (37%) and fatigue (25%). In the dose escalation part, objective responses occurred in 3/33 patients treated with CV8102 as monotherapy and in 2/25 patients treated with CV8102 plus a PD-1 inhibitor. In the expansion cohorts in patients with anti-PD-1 therapy-refractory melanoma, 0/10 patients treated with CV8102 as monotherapy and 5/30 patients (17%) treated in combination with a PD-1 inhibitor experienced objective responses., Conclusions: IT CV8102 was generally well tolerated with preliminary signs of efficacy as monotherapy and in combination with a PD-1 inhibitor., Trial Registration Number: NCT03291002., Competing Interests: Competing interests: TE and IT have received institutional funding for the work in this study. YS, IS, ME, LH, JK, AO, CW, PM, CLP, PB, MF, AP, MS and AS have no competing interests. CR is an occasional consultant for Roche, BMS, MSD, Sanofi, Pierre Fabre, AstraZeneca, and Novartis. CL has received consulting fees from BMS, MSD, Sanofi, Immunocore, and Pierre Fabre. JM-L has received consulting fees from Bristol-Myers Squibb, Highlight Therapeutics, Novartis, Pierre Fabre, Roche, and Sanofi. ER has received consulting fees from BMS, MSD, Novartis, and Pierre Fabre; speakers’ fees from Amgen, BMS, Delcath, MSD, Merck, Novartis, Pierre Fabre, Sanofi, Amgen, BMS, Curevac, Delcath, Incyte, MSD, Merck, Novartis, Pierre Fabre, Regeneron and Roche. PT has received consulting fees from Almirall, BMS, Kyowa Kirin, Merck, Novartis, Pierre Fabre, Sanofi, 4SC, and honorarium from Almirall, BMS, Biofrontera, Kyowa Kirin, Merck, Novartis, Pierre Fabre, Roche, Sanofi, and 4SC. BS-B, MG, JH, PW, TS, SDK, GQ, PC, MF, and UG-V are employees of CureVac SE. OS-K and SO have received consulting fees from CureVac SE., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response., Patients and Methods: A total of 82 patients with very early- to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints., Results: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against ≥1 vaccinated HLA class I tumor-associated peptide (TAA) and ≥1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees., Conclusions: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted., (©2022 American Association for Cancer Research.)

CV9201 is an RNActive ® -based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400-1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo T cell responses against the five antigens, and changes in immune cell populations. All CV9201 dose levels were well-tolerated and the recommended dose for phase IIa was 1600 µg. Most AEs were mild-to-moderate injection site reactions and flu-like symptoms. Three (7%) patients had grade 3 related AEs. No related grade 4/5 or related serious AEs occurred. In phase IIa, antigen-specific immune responses against ≥ 1 antigen were detected in 63% of evaluable patients after treatment. The frequency of activated IgD + CD38 hi B cells increased > twofold in 18/30 (60%) evaluable patients. 9/29 (31%) evaluable patients in phase IIa had stable disease and 20/29 (69%) had progressive disease. Median progression-free and overall survival were 5.0 months (95% CI 1.8-6.3) and 10.8 months (8.1-16.7) from first administration, respectively. Two- and 3-year survival rates were 26.7% and 20.7%, respectively. CV9201 was well-tolerated and immune responses could be detected after treatment supporting further clinical investigation.

Background: We report the first-in-concept human trial of the safety, tolerability and immunogenicity when a novel TLR 7/8/RIG I agonist RNA-based adjuvant, CV8102, was administered alone or mixed with fractional doses of a licensed rabies vaccine (Rabipur®) as model antigen., Methods: The primary objective was to assess the safety and reactogenicity of various dose levels of CV8102 alone or mixed with Rabipur® in healthy 18-40 year-old male volunteers. A secondary objective was to assess the immune-enhancing potential of bedside-mixes of CV8102 with fractional doses of Rabipur® by measuring induction of rabies virus neutralising titres (VNTs)., Results: Fifty-six volunteers received 50-100 μg CV8102 alone (n = 11), bedside-mixed CV8102 and Rabipur® (n = 20), or Rabipur® alone (n = 25; control). When given alone or mixed with Rabipur® CV8102 caused mostly Grade 1 or 2 local or systemic reactogenicity, but no related SAEs. As 100 µg CV8102 was associated with marked CRP increases further dose escalation was stopped. Combining 25-50 µg of CV8102 with fractional doses of Rabipur® significantly improved the kinetics of VNT responses; 50 µg CV8102 also improved the magnitude of VNT responses to 1/10 Rabipur® but caused severe but self-limiting influenza-like symptoms in 2 of 14 subjects., Conclusions: Doses of 25 and 50 µg CV8102 appeared safe and with an acceptable reactogenicity profile while significantly enhancing the immunogenicity of fractional doses of rabies vaccine. EudraCT No. 2013-004514-18., (Copyright © 2019. Published by Elsevier Ltd.)

Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses., Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61)., Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions., Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors., Trial Registration: ClinicalTrials.gov identifier: NCT01915524 .

Background: Vaccines based on mRNA coding for antigens have been shown to be safe and immunogenic in preclinical models. We aimed to report results of the first-in-human proof-of-concept clinical trial in healthy adults of a prophylactic mRNA-based vaccine encoding rabies virus glycoprotein (CV7201)., Methods: We did an open-label, uncontrolled, prospective, phase 1 clinical trial at one centre in Munich, Germany. Healthy male and female volunteers (aged 18-40 years) with no history of rabies vaccination were sequentially enrolled. They received three doses of CV7201 intradermally or intramuscularly by needle-syringe or one of three needle-free devices. Escalating doses were given to subsequent cohorts, and one cohort received a booster dose after 1 year. The primary endpoint was safety and tolerability. The secondary endpoint was to determine the lowest dose of CV7201 to elicit rabies virus neutralising titres equal to or greater than the WHO-specified protective antibody titre of 0·5 IU/mL. The study is continuing for long-term safety and immunogenicity follow-up. This trial is registered with ClinicalTrials.gov, number NCT02241135., Findings: Between Oct 21, 2013, and Jan 11, 2016, we enrolled and vaccinated 101 participants with 306 doses of mRNA (80-640 μg) by needle-syringe (18 intradermally and 24 intramuscularly) or needle-free devices (46 intradermally and 13 intramuscularly). In the 7 days post vaccination, 60 (94%) of 64 intradermally vaccinated participants and 36 (97%) of 37 intramuscularly vaccinated participants reported solicited injection site reactions, and 50 (78%) of 64 intradermally vaccinated participants and 29 (78%) of 37 intramuscularly vaccinated participants reported solicited systemic adverse events, including ten grade 3 events. One unexpected, possibly related, serious adverse reaction that occurred 7 days after a 640 μg intramuscular dose resolved without sequelae. mRNA vaccination by needle-free intradermal or intramuscular device injection induced virus neutralising antibody titres of 0·5 IU/mL or more across dose levels and schedules in 32 (71%) of 45 participants given 80 μg or 160 μg CV7201 doses intradermally and six (46%) of 13 participants given 200 μg or 400 μg CV7201 doses intramuscularly. 1 year later, eight (57%) of 14 participants boosted with an 80 μg needle-free intradermal dose of CV7201 achieved titres of 0·5 IU/mL or more. Conversely, intradermal or intramuscular needle-syringe injection was ineffective, with only one participant (who received 320 μg intradermally) showing a detectable immune response., Interpretation: This first-ever demonstration in human beings shows that a prophylactic mRNA-based candidate vaccine can induce boostable functional antibodies against a viral antigen when administered with a needle-free device, although not when injected by a needle-syringe. The vaccine was generally safe with a reasonable tolerability profile., Funding: CureVac AG., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We recently completed a phase I/IIa trial of RNActive® CV9201, a novel mRNA-based therapeutic vaccine targeting five tumor-associated antigens in non-small cell lung cancer (NSCLC) patients. The aim of the study presented here was to comprehensively analyze changes in peripheral blood during the vaccination period and to generate hypotheses facilitating the identification of potential biomarkers correlating with differential clinical outcomes post RNActive® immunotherapy. We performed whole-genome expression profiling in a subgroup of 22 stage IV NSCLC patients before and after initiation of treatment with CV9201. Utilizing an analytic approach based on blood transcriptional modules (BTMs), a previously described, sensitive tool for blood transcriptome data analysis, patients segregated into two major clusters based on transcriptional changes post RNActive® treatment. The first group of patients was characterized by the upregulation of an expression signature associated with myeloid cells and inflammation, whereas the other group exhibited an expression signature associated with T and NK cells. Patients with an enrichment of T and NK cell modules after treatment compared to baseline exhibited significantly longer progression-free and overall survival compared to patients with an upregulation of myeloid cell and inflammatory modules. Notably, these gene expression signatures were mutually exclusive and inversely correlated. Furthermore, our findings correlated with phenotypic data derived by flow cytometry as well as the neutrophil-to-lymphocyte ratio. Our study thus demonstrates non-overlapping, distinct transcriptional profiles correlating with survival warranting further validation for the development of biomarker candidates for mRNA-based immunotherapy.

Previous cancer vaccination trials often aimed to activate CD8(+) cytotoxic T-cell (CTL) responses with short (8-10mer) peptides and targeted CD4(+) helper T cells (TH) with HLA class II-binding longer peptides (12-16 mer) that were derived from tumor antigens. Accordingly, a study of immunomonitoring focused on the detection of CTL responses to the short, and TH responses to the long, peptides. The possible induction of concurrent TH responses to short peptides was widely neglected. In a recent phase I vaccination trial, 53 patients with different solid cancers were vaccinated with EMD640744, a cocktail of five survivin-derived short (9- or 10-mer) peptides in Montanide ISA 51VG. We monitored 49 patients and found strong CD8(+) T-cell responses in 63% of the patients. In addition, we unexpectedly found CD4(+) TH cell responses against at least two of the five short peptides in 61% (23/38) of the patients analyzed. The two peptides were recognized by HLA-DP4- and HLA-DR-restricted TH1 cells. Some short peptide-reactive (sp)CD4 T cells showed high functional avidity. Here, we show that a short peptide vaccine is able to activate a specific CD4(+) T-cell repertoire in many patients, facilitating a strong combined CD4(+)/CD8(+) T-cell response., (©2015 American Association for Cancer Research.)

Background: CV9103 is a prostate-cancer vaccine containing self-adjuvanted mRNA (RNActive®) encoding the antigens PSA, PSCA, PSMA, and STEAP1. This phase I/IIa study evaluated safety and immunogenicity of CV9103 in patients with advanced castration-resistant prostate-cancer., Methods: 44 Patients received up to 5 intra-dermal vaccinations. Three dose levels of total mRNA were tested in Phase I in cohorts of 3-6 patients to determine a recommended dose. In phase II, 32 additional patients were treated at the recommended dose. The primary endpoint was safety and tolerability, the secondary endpoint was induction of antigen specific immune responses monitored at baseline and at weeks 5, 9 and 17., Results: The most frequent adverse events were grade 1/2 injection site erythema, injection site reactions, fatigue, pyrexia, chills and influenza-like illness. Possibly treatment related urinary retention occurred in 3 patients. The recommended dose was 1280 μg. A total of 26/33 evaluable patients treated at 1280 μg developed an immune response, directed against multiple antigens in 15 out of 33 patients. One patient showed a confirmed PSA response. In the subgroup of 36 metastatic patients, the Kaplan-Meier estimate of median overall survival was 31.4 months [95 % CI: 21.2; n.a]., Conclusions: The self-adjuvanted RNActive® vaccine CV9103 was well tolerated and immunogenic. The technology is a versatile, fast and cost-effective platform allowing for creation of vaccines. The follow-up vaccine CV9104 including the additional antigens prostatic acid phosphatase (PAP) and Muc1 is currently being tested in a randomized phase IIb trial to assess the clinical benefit induced by this new vaccination approach., Trial Registration: EU Clinical Trials Register: EudraCT number 2008-003967-37, registered 27 Jan 2009.

Background: Advanced non-small cell lung cancer (NSCLC) represents a significant unmet medical need. Despite advances with targeted therapies in a small subset of patients, fewer than 20% of patients survive for more than two years after diagnosis. Cancer vaccines are a promising therapeutic approach that offers the potential for durable responses through the engagement of the patient's own immune system. CV9202 is a self-adjuvanting mRNA vaccine that targets six antigens commonly expressed in NSCLC (NY-ESO-1, MAGEC1, MAGEC2, 5 T4, survivin, and MUC1)., Methods/design: The trial will assess the safety and tolerability of CV9202 vaccination combined with local radiation designed to enhance immune responses and will include patients with stage IV NSCLC and a response or stable disease after first-line chemotherapy or therapy with an EGFR tyrosine kinase inhibitor. Three histological and molecular subtypes of NSCLC will be investigated (squamous and non-squamous cell with/without EGFR mutations). All patients will receive two initial vaccinations with CV9202 prior to local radiotherapy (5 GY per day for four successive days) followed by further vaccinations until disease progression. The primary endpoint of the study is the number of patients experiencing Grade >3 treatment-related adverse events. Pharmacodynamic analyses include the assessment of immune responses to the antigens encoded by CV9202 and others not included in the panel (antigen spreading) and standard efficacy assessments., Discussion: RNActive self-adjuvanted mRNA vaccines offer the potential for simultaneously inducing immune responses to a wide panel of antigens commonly expressed in tumors. This trial will assess the feasibility of this approach in combination with local radiotherapy in NSCLC patients., Trial Registration: Clinicaltrials.gov: NCT01915524/EudraCT No.: 2012-004230-41.

Purpose: Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin-vaccine-induced immune responses., Experimental Design: This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I-binding survivin peptides in Montanide(®) ISA 51 VG, promotes anti-survivin T-cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 μg. Secondary objectives included safety, tolerability, and clinical efficacy., Results: In total, 49 patients who received ≥2 EMD640744 injections with available baseline- and ≥1 post-vaccination samples [immunologic-diagnostic (ID)-intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection-site reactions constituted the most frequent adverse event., Conclusions: Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744.

The efficacy of combination therapy with irinotecan and capecitabine has been demonstrated for the first-line treatment of metastatic colorectal cancer (MCRC). The aim of this trial was to evaluate the efficacy and safety of this combination in MCRC as second-line treatment after failure of 24-h infusional 5-fluorouracil (5-FU24h) and folinic acid (FA). Patients pre-treated with 5-FU24h/FA were recruited at two institutions to receive 6 x weekly irinotecan 70 mg/m2 and capecitabine (1000 mg/m2 b.i.d. days 1-14 and 22-35). Courses were repeated on day 50. In elderly patients (>65 years) a 20% dose reduction of both drugs was scheduled. Twenty-eight patients [M/F 20/8; median age 65 years (range 44-79); median ECOG score 1] were enrolled. The most frequent sites of metastases were liver, n=20, lymph nodes and lungs, n=10, respectively. Half of the patients had two or more metastatic sites. A total of 71 treatment courses (median 2, range 1-8) were administered. Main toxicities [worst per patient (%); CTC grade 1/2/3/4] were: anaemias 18/14/-/-; leukocytopenia 11/21/-/-; thrombocytopenia 11/-/-/-; diarrhea 18/36/21/-; nausea/vomiting 43/29/4/-; mucositis 4/11/-/-; alopecia 7/25/-/-; hand-foot syndrome 7/21/-/-; fatigue 14/14/-/-; renal insufficiency (caused by diarrhea and exsiccosis) -/-/-/7. Dose intensity in the first course was [median/mean (%)]: irinotecan 92/83; capecitabine 88/82. Twenty-three patients are evaluable for response analysis (five did not complete the first course): three patients showed partial remissions (13%) and 11 patients had stable disease (48%). Median time to progression was 3.0 months for the total population (range 1.4-17.3) and 6.5 months for responders (partial response plus no change). Seventy-four percent of the patients received a third-line therapy. Overall survival was 15.7 months calculated from the start of study treatment. Second-line therapy with irinotecan and capecitabine yielded a tumor control in 61% of patients with MCRC. Efficacy and toxicity data are comparable to 5-FU/irinotecan combinations, although the likelihood of severe diarrhea appears to be higher with capecitabine/irinotecan.