Immunotherapy advances最新文献

Immune checkpoint inhibitors are one of the most remarkable immunomodulatory therapies of current times. Sabatolimab is a high-affinity, humanized anti-TIM-3 monoclonal antibody currently in development for patients with myeloproliferative disorders, including acute myeloid leukemia and myelodysplastic syndromes. By targeting TIM-3, a receptor expressed on various immune effector cells as well as myeloid cells, multiple mechanisms of action that are distinct from canonical immune checkpoint inhibitors are in play - (i) blockade of TIM-3 and its ligands PtdSer/galectin-9, (ii) modulation of leukemic cell self-renewal as well as (iii) antibody-dependent phagocytosis of TIM-3-expressing leukemic cells. Novel immunotherapies such as sabatolimab which enhance the antitumor immune response on converging fronts represent the promise of a continuously replenished armoury for the treatment of cancer.

Background: Cutaneous immune-related adverse events (irAEs) are the most common irAEs caused by immune-checkpoint inhibitors (ICI). Psoriasiform eruptions, both de novo and flares, may occur. Evidence is lacking on inverse psoriasis subtype.

Methods: A retrospective study was conducted at Dana-Farber Cancer Institute/Mass General Brigham through February 2020 using databases. Confirmed inverse psoriasis cases pre-/post-ICI initiation either independently or in conjunction with other psoriasis subtypes were included. Known psoriasis cases without flare post-ICI were excluded.

Results: A total of 262 (3%) individuals with any ICI-mediated psoriasiform cutaneous irAE were identified out of the 8683 DFCI ICI-treated patients. Of these, 13 (5% of psoriasis patients) had inverse psoriasis (mean age 68.7 years; 7/13 male sex). Median (range) time from ICI initiation to inverse psoriasis development or flare was 7 (4-12) and 3.5 (2-6) weeks, respectively. Pruritus occurred in 12/13 (92.30%) cases. 11 (85%) had inguinal involvement; other sites included gluteal cleft (6; 46%), inframammary (3; 23%), perianal (2; 15%), axilla (2; 15%), umbilicus (2; 15%), and infra-abdominal folds (1; 8%). Most (9/13) individuals had more than one site involved. The Common Terminology Criteria for Adverse Events severity was 1 in 10 (76.92%) individuals and 2 in 3 (15.38%) individuals. Six (46.15%) patients were treated initially by oncology with topical (nystatin, econazole, or clotrimazole) or systemic antifungals (fluconazole) for median (range) of 3.5 (1-7) months without improvement, for presumed candida intertrigo.

Conclusion: Patients on ICI may develop inverse psoriasis, which may be initially confused for fungal intertrigo. Delayed diagnosis can prolong symptoms, while patients are treated ineffectively with topical/systemic antifungals for presumed candida infection. Oncologist and dermatologist awareness is important to improve diagnosis of ICI-mediated inverse psoriasis, its management and affected patients' quality of life.

Currently, treatments for rheumatoid arthritis (RA) are focussed on management of disease symptoms rather than addressing the cause of disease, which could lead to remission and cure. Central to disease development is the induction of autoimmunity through a breach of self-tolerance. Developing approaches to re-establish antigen specific tolerance is therefore an important emerging area of RA research. A crucial step in this research is to employ appropriate animal models to test prospective antigen specific immunotherapies. In this short communication, we evaluate our previously developed model of antigen specific inflammatory arthritis in which ovalbumin-specific T cell receptor transgenic T cells drive breach of tolerance to endogenous antigens to determine the impact that the timing of therapy administration has upon disease progression. Using antigen feeding to induce tolerance we demonstrate that administration prior to articular challenge results in a reduced disease score as evidenced by pathology and serum antibody responses. By contrast, feeding antigen after initiation of disease had the opposite effect and resulted in the exacerbation of pathology. These preliminary data suggest that the timing of antigen administration may be key to the success of tolerogenic immunotherapies. This has important implications for the timing of potential tolerogenic therapies in patients.

Drug development typically comprises a combination of pre-clinical experimentation, clinical trials, and statistical data-driven analyses. Therapeutic failure in late-stage clinical development costs the pharmaceutical industry billions of USD per year. Clinical trial simulation represents a key derisking strategy and combining them with mechanistic models allows one to test hypotheses for mechanisms of failure and to improve trial designs. This is illustrated with a T-cell activation model, used to simulate the clinical trials of IMA901, a short-peptide cancer vaccine. Simulation results were consistent with observed outcomes and predicted that responses are limited by peptide off-rates, peptide competition for dendritic cell (DC) binding, and DC migration times. These insights were used to hypothesise alternate trial designs predicted to improve efficacy outcomes. This framework illustrates how mechanistic models can complement clinical, experimental, and data-driven studies to understand, test, and improve trial designs, and how results may differ between humans and mice.

[This corrects the article DOI: 10.1093/immadv/ltaa002.][This corrects the article DOI: 10.1093/immadv/ltab010.][This corrects the article DOI: 10.1093/immadv/ltaa007.].

Many different types of cancer are now well known to have increased occurrence or severity in individuals with obesity. The influence of obesity on cancer and the immune cells in the tumor microenvironment has been thought to be a pleiotropic effect. As key endocrine and immune organs, the highly plastic adipose tissues play crucial roles in obesity pathophysiology, as they show alterations according to environmental cues. Adipose tissues of lean subjects present mostly anti-inflammatory cells that are crucial in tissue remodeling, favoring uncoupling protein 1 expression and non-shivering thermogenesis. Oppositely, obese adipose tissues display massive proinflammatory immune cell infiltration, dying adipocytes, and enhanced crown-like structure formation. In this review, we discuss how obesity can lead to derangements and dysfunctions in antitumor CD8+ T lymphocytes dysfunction. Moreover, we explain how obesity can affect the efficiency of cancer immunotherapy, depicting the mechanisms involved in this process. Cancer immunotherapy management includes monoclonal antibodies targeting the immune checkpoint blockade. Exhausted CD8+ T lymphocytes show elevated programmed cell death-1 (PD-1) expression and highly glycolytic tumors tend to show a good response to anti-PD-1/PD-L1 immunotherapy. Although obesity is a risk factor for the development of several neoplasms and is linked with increased tumor growth and aggressiveness, obesity is also related to improved response to cancer immunotherapy, a phenomenon called the obesity paradox. However, patients affected by obesity present higher incidences of adverse events related to this therapy. These limitations highlight the necessity of a deeper investigation of factors that influence the obesity paradox to improve the application of these therapies.

[This corrects the article DOI: 10.1093/immadv/ltab024.].

The development of novel chimeric antigen receptor (CAR) cell therapies is rapidly growing, with 299 new agents being reported and 109 new clinical trials initiated so far this year. One critical lesson from approved CD19-specific CAR therapies is that target isoform switching has been shown to cause tumour relapse, but little is known about the isoforms of CAR targets in solid cancers. Here we assess the protein isoform landscape and identify both the challenges and opportunities protein isoform switching present as CAR therapy is applied to solid cancers.