Experimental studies of the effect of cancer chemotherapy on cellular immunity and its modification.

The experimental evidence for an immune response to cancer has been reviewed, and the effects of cytotoxic chemotherapy shown to affect nearly all of its aspects. Augmentation of the immune response (immunotherapy) has been discussed in the context of several important agents. It is argued that in advanced cancers the tumour burden is too great for significant benefit from immunotherapy. However in patients with 'minimal residual disease' there is little evidence for impairment of immune responses. When such patients receive adjuvant chemotherapy the number of residual cancer cells is further reduced, but the patient's immunological ability to complete their elimination is seriuosly impaired by the treatment. This situation may be a most suitable opportunity to achieve benefit from immunotherapy, and this study concerns attempts to identify means of achieving this. The work is concentrated on one major arm of the immune response, both in normal rats and some in whom breast cancers were induced. T lymphocyte function was measured in rats by an in vivo (DTH response) and an in vitro (PHA blastogenesis) method. Clear depression was seen following one injection of cyclophosphamide or 5 fluorouracil (5FU) in both normal and tumour bearing animals, and this lasted for at least one month (PHA). The rebound overshoot phenomenon was observed in both groups following 5FU but not cyclophosphamide. Levamisole did not improve the depression of in vitro T cell function produced by cyclophosphamide, but alleviated that following 5FU if administerd after a delay of 3 days. This effect was somewhat marginal but seen consistently in both normal and tumour bearing animals. The combination of glucan with either cytotoxic agent significantly worsened in vitro T cell function, even if the timing of each drug was varied. This observation is interpreted as a directly depressive effect of glucan on T cell function, revealed only in conjunction with cytotoxic therapy. A similar effect was also seen following C parvum but not thiabendazole. The use of a small priming dose of either chemotherapeutic agent did not alleviate the immunosuppressive effect of a subsequently administered large dose. Wide variation of the priming delay for cyclophosphamide did not alter this conclusion. Similarly no benefit was gained either from the regular administration of cimetidine, or the timing of cytotoxic injections to opposing extremes of diurnal rhythms. The difficulties encountered in this field of research and questions for future study are discussed

A Dipolar Cycloaddition Reaction To Access 6‑Methyl-4,5,6,7-tetrahydro‑1<i>H</i>‑[1,2,3]­triazolo[4,5‑<i>c</i>]­pyridines Enables the Discovery Synthesis and Preclinical Profiling of a P2X7 Antagonist Clinical Candidate

A single pot dipolar cycloaddition reaction/Cope elimination sequence was developed to access novel 1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridine P2X7 antagonists that contain a synthetically challenging chiral center. The structure–activity relationships of the new compounds are described. Two of these compounds, (<i>S</i>)-(2-fluoro-3-(trifluoromethyl)­phenyl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>29</b>) and (<i>S</i>)-(3-fluoro-2-(trifluoromethyl)­pyridin-4-yl)­(1-(5-fluoropyrimidin-2-yl)-6-methyl-1,4,6,7-tetrahydro-5<i>H</i>-[1,2,3]­triazolo­[4,5-<i>c</i>]­pyridin-5-yl)­methanone (compound <b>35</b>), were found to have robust P2X7 receptor occupancy at low doses in rat with ED₅₀ values of 0.06 and 0.07 mg/kg, respectively. Compound <b>35</b> had notable solubility compared to <b>29</b> and showed good tolerability in preclinical species. Compound <b>35</b> was chosen as a clinical candidate for advancement into phase I clinical trials to assess safety and tolerability in healthy human subjects prior to the initiation of proof of concept studies for the treatment of mood disorders

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p