Idiotypic DNA vaccination for the treatment of multiple myeloma: safety and immunogenicity in a phase I clinical study

We report on the safety and immunogenicity of idiotypic DNA vaccination in a phase I, non-randomised, open-label study in patients with multiple myeloma. The study used DNA fusion gene vaccines encoding patient-specific single chain variable fragment, or idiotype (Id), linked to fragment C (FrC) of tetanus toxin. Patients in complete or partial response following high-dose chemotherapy and autologous stem cell transplant were vaccinated intramuscularly with 1 mg DNA on six occasions, beginning at least 6 months post-transplant; follow-up was to week 52. Fourteen patients were enrolled on study and completed vaccinations. Idiotypic DNA vaccines were well tolerated with vaccine-related adverse events limited to low-grade constitutional symptoms. FrC- and Id-specific T-cell responses were detected by ex vivo ELISPOT in 9/14 and 3/14 patients, respectively. A boost of pre-existing anti-FrC antibody (Ab) was detected by ELISA in 8/14 patients, whilst anti-Id Ab was generated in 1/13 patients. Overall, four patients (29 %) made an immune response to FrC and Id, with six patients (43 %) responding to FrC alone. Over the 52-week study period, serum paraprotein was undetectable, decreased or remained stable for ten patients (71 %), whilst ongoing CR/PR was maintained for 11 patients (79 %). The median time to progression was 38.0 months for 13/14 patients. Overall survival was 64 % after a median follow-up of 85.6 months

Rationale and methods of a randomized trial evaluating the effect of neprilysin inhibition on left ventricular remodelling

Aims: In patients at high risk of heart failure following myocardial infarction (MI) as a result of residual left ventricular systolic dysfunction (LVSD), the angiotensin receptor neprilysin inhibitor sacubitril/valsartan may result in a greater attenuation of adverse left ventricular (LV) remodelling than renin angiotensin aldosterone system inhibition alone, due to increased levels of substrates for neprilysin with vasodilatory, anti‐hypertrophic, anti‐fibrotic, and sympatholytic effects. Methods: We designed a randomized, double‐blinded, active‐comparator trial to examine the effect of sacubitril/valsartan to the current standard of care in reducing adverse LV remodelling in patients with asymptomatic LVSD following MI. Eligible patients were ≥3 months following MI, had an LV ejection fraction ≤40% as measured by echocardiography, were New York Heart Association functional classification I, tolerant of an angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker at equivalent dose of ramipril 2.5 mg twice daily or greater, and taking a beta‐blocker unless contraindicated or intolerant. Patients were randomized to sacubitril/valsartan (target dose 97/103 mg twice daily) or valsartan (target dose 160 mg twice daily). The primary endpoint will be change in LV end‐systolic volume indexed for body surface area measured using cardiac magnetic resonance imaging over 52 weeks from randomization. Secondary endpoints include other magnetic resonance imaging‐based metrics of LV remodelling, biomarkers associated with LV remodelling and neurohumoral activation, and change in patient well‐being assessed using a patient global assessment questionnaire. Conclusions: This trial will investigate the effect of neprilysin inhibition on LV remodelling and the neurohumoral actions of sacubitril/valsartan in patients with asymptomatic LVSD following MI

The effect of neprilysin inhibition on left ventricular remodeling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction

Background: Patients with left ventricular systolic dysfunction (LVSD) following myocardial infarction (MI) are at high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system (RAS) inhibition may result in greater attenuation of adverse LV remodeling due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. Methods: We performed a prospective, multi-center, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients ≥3 months following MI with a LV ejection fraction (LVEF) ≤40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association functional classification ≥II or with signs and symptoms of HF were excluded. The primary outcome was change from baseline to 52-weeks in LV end-systolic volume index (LVESVI) measured using cardiac magnetic resonance imaging (MRI). Secondary outcomes included other MRI measurements of LV remodeling, change in N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI), and a patient global assessment of change questionnaire. Results: From July 2018 to June 2019, 93 patients were randomized: mean age 60.7±10.4 years, median time from MI 3.6 years (IQR 1.2-7.2), mean LVEF 36.8%±7.1, median NT-proBNP 230pg/mL (124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; adjusted between-group difference -1.9mL/m2 (95%CI -4.9, 1.0); p=0.19. There were no significant between-group differences in NT-proBNP, hs-TnI, LV end-diastolic volume index, left atrial volume index, LVEF, LV mass index, or patient global assessment of change. Conclusions: In patients with asymptomatic LVSD following MI, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT0355257

Linked CD4 T cell help: broadening immune attack against cancer by vaccination

In the last decade, immunotherapy with monoclonal antibodies targeting immunological check points has become a breakthrough therapeutic modality for solid cancers. However, only up to 50 % of patients benefit from this powerful approach. For others vaccination might provide a plausible addition or alternative. For induction of effective anticancer immunity CD4+ T cell help is required, which is often difficult to induce to self cancer targets because of tolerogenic mechanisms. Our approach for cancer vaccines has been to incorporate into the vaccine design sequences able to activate foreign T cell help, through genetically linking cancer targets to microbial sequences (King et al. in Nat Med 4(11):1281–1286, 1998; Savelyeva et al. in Nat Biotechnol 19(8):760–764, 2001). This harnesses the non-tolerized CD4 T cell repertoire available in patients to help induction of effective immunity against fused cancer antigens. Multiple immune effector mechanisms including antibody, CD8+ T cells as well as CD4 effector T cells can be activated using this strategy. Delivery via DNA vaccines has already indicated clinical efficacy. The same principle of linked T cell help has now been transferred to other novel vaccine modalities to further potentiate immunity against cancer targets