Relief Therapeutics Holding AG (RLFTF)

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Here is the NEW ENGLAND JOURNAL OF MEDICINE Article on the use of AVIPTADIL (specified as produced by BACHEM) with cancer patients developing pneumonia in the course of chemotherapy:
Vasoactive Intestinal Peptide in Checkpoint Inhibitor–Induced Pneumonitis

DOI: 10.1056/NEJMc2000343

Link: https://www.nejm.org/doi/10.1056/NEJMc2000343

TO THE EDITOR:
Therapy with immune checkpoint inhibitors has become a new therapeutic option for several types of cancer, but immune-related adverse events can limit their use.1 Outside of clinical studies, pneumonitis develops in as many as 10 to 20% of patients who are treated with immune checkpoint inhibitors, a complication leading to discontinuation of the treatment and to immunosuppressive therapy.1,2

Figure 1.

https://www.nejm.org/na101/home/literatum/publisher/mms/journals/content/nejm/2020/nejm_2020.382.issue-26/nejmc2000343/20200624/images/img_small/nejmc2000343_f1.jpeg

Radiologic Imaging before and during Treatment with Vasoactive Intestinal Peptide.
A 68-year-old man who was treated with pembrolizumab for advanced melanoma (a case report is provided in the Supplementary Appendix, available with the full text of this letter at NEJM.org) had recurrent pneumonitis even after treatment discontinuation and receipt of glucocorticoid treatment in accordance with current guidelines.1 His respiratory and general symptoms were quantified with the King’s Sarcoidosis Questionnaire, and he was found to have decreased values for the general health and lung domains. Computed tomography showed widespread consolidations (Figure 1A), a finding compatible with recurrent immune checkpoint inhibitor pneumonitis. Analysis of bronchoalveolar lavage (BAL) fluid ruled out infection but revealed a lymphocytosis with decreased regulatory T cells, as has been described in immune checkpoint inhibitor pneumonitis.3 (Details regarding health assessments, lung-function measures, imaging, and cytometric analyses referred to in this report, from before treatment and during follow-up, are provided in Figs. S1 through S5 in the Supplementary Appendix.)

Treatment with an inhaled formulation of synthetic vasoactive intestinal peptide (Aviptadil, Bachem) was initiated, at a dose of 70 µg three times daily, as an alternative treatment to avoid glucocorticoid-related side effects and systemic immunosuppression. Vasoactive intestinal peptide has been shown to dampen type 1 helper T cell (Th1) responses by inhibiting effector T cells and boosting regulatory T cells through its G-protein–coupled receptors (VPAC1 and VPAC2). Its inhaled application in sarcoidosis increases alveolar regulatory T cells and reduces proinflammatory cytokines, resulting in clinical improvement.4

Treatment with inhaled vasoactive intestinal peptide resulted in clinical and radiologic improvement in the lungs (Figure 1B). Analysis of BAL fluid showed reduced alveolar lymphocytosis with reduced CD28 expression and increased regulatory T cells. Spontaneous and lipopolysaccharide-induced release of tumor necrosis factor, reflecting the inflammatory alveolar milieu, were dampened during treatment. Vasoactive intestinal peptide was not associated with toxic effects and did not influence lymphocyte subtypes in peripheral blood (Table S1). Eight weeks after cessation of the treatment, the patient had systemic nonpulmonary progression of melanoma disease.

Our findings support inhaled vasoactive intestinal peptide as a local therapy to reduce the alveolar inflammation found in patients with immune checkpoint inhibitor pneumonitis. Whether this therapy has an influence on tumor progression cannot be determined on the basis of this case. However, further studies are indicated to investigate whether vasoactive intestinal peptide may be a therapeutic option for immune checkpoint inhibitor pneumonitis.

Björn C. Frye, M.D.
Frank Meiss, M.D.
Dagmar von Bubnoff, M.D.
Gernot Zissel, Ph.D.
Joachim Müller-Quernheim, M.D.
University Medical Center Freiburg, Freiburg, Germany