A phase I clinical trial of RNF43 peptide-related immune cell therapy combined with low-dose cyclophosphamide in patients with advanced solid tumors

Abstract

The objective of this study was to investigate the safety and the tolerability of combined cellular immunotherapy with low-dose cyclophosphamide (CPA) in patients with advanced solid tumors. This study targeted a novel tumor-associated antigen, ring finger protein 43 (RNF43). Eligible patients were resistant to standard therapy, HLA-A*24:02- or A*02:01-positive and exhibiting high RNF43 expression in their tumor cells. They were administered 300 mg/m2 CPA followed by autologous lymphocytes, preliminarily cultured with autologous RNF43 peptide-pulsed dendritic cells (DCs), RNF43 peptide-pulsed DCs and systemic low dose interleukin-2. The primary endpoint was safety whereas the secondary endpoint was immunological and clinical response to treatment. Ten patients, in total, were enrolled in this trial. Primarily, no adverse events greater than Grade 3 were observed. Six out of 10 patients showed stable disease (SD) on day 49, while 4 other patients showed progressive disease. In addition, one patient with SD exhibited a partial response after the second trial. The frequency of regulatory T cells (Tregs) in patients with SD significantly decreased after CPA administration. The ratio of interferon-γ-producing, tumor-reactive CD8+ T cells increased with time in patients with SD. We successfully showed that the combination of immune cell therapy and CPA was safe, might induce tumor-specific immune responses and clinical efficacy, and was accompanied by a decreased ratio of Tregs in patients with RNF43-positive advanced solid tumors.

Trial watch: dendritic cell vaccination for cancer immunotherapy

“…The majority of these studies (Figure 1) tested autologous DCs pulsed with: TAAs or peptides thereof, [325][326][327][328][329][330][331][332][333][334][335][336][337][338][339][340][341][342] autologous cancer cell lysates, [343][344][345][346][347][348] or TAA-coding RNAs. 276,[349][350][351][352] The predominant use of these TAA sources for the generation of DC-based vaccines is in line with previous trends, as documented in our previous Trial Watch on this subject, 279 de facto reflecting a broad consensus in the field.…”

“…While most of these clinical studies were basket trials enrolling patients with multiple solid tumors (Figure 1), 326,331,336,348 studies focusing on single indications most commonly enrolled patients with melanoma, 332,337,339,343 prostate cancer, 276,325,329,353 or glioblastoma (GBM). 341,346,350,352 This was followed by pancreatic cancer, 327,333,358 non-small cell lung carcinoma (NSCLC), 338,340,354 and myeloma 330,334,345 (Figure 1).…”

“…In most clinical studies, DC vaccines were administered in combination with standard-of-care 348 or off-label chemotherapeutics (e.g., gemcitabine, cyclophosphamide, S-1, temozolomide, carboplatin, paclitaxel or docetaxel), 276,[326][327][328]337,338,341,344,346,350,358 radiotherapy, 335,341,346 targeted anticancer agents (e.g., tyrosine kinase inhibitors), 328,344 or specific immunotherapeutic regimens, including recombinant colony stimulating factor 2 (CSF2, best known as GM-CSF), recombinant IL2, ACT, and TL3 agonists. 326,333,344,352,353 Importantly, the vast majority of these clinical studies confirmed that DC-based vaccines are safe for cancer patients, 359 causing mild-to-moderate side effects including fever, erythema, flu-like symptoms, rash and/or fatigue, in a small proportion of patients. 328,333,335,340,341,348 Signs of ongoing TAA-or tumortargeting effector responses upon vaccination, including (but not limited to) increased antigen-specific T-or B-cell activity and tumor infiltration by CD8 + CTLs, were consistently documented.…”

“…328,333,335,340,341,348 Signs of ongoing TAA-or tumortargeting effector responses upon vaccination, including (but not limited to) increased antigen-specific T-or B-cell activity and tumor infiltration by CD8 + CTLs, were consistently documented. 327,332,355 Moreover, multiple clinical studies reported promising clinical responses to vaccination, including disease stabilization 326,328,333,342,344,354 as well as a few partial and complete responses. 330,335,345,[347][348][349] Encouragingly, a few cases of robust extension in patient survival were also documented.…”

Development of Peptide-Based Vaccines for Cancer

“…Cyclophosphamide is a chemotherapeutic drug that has direct cytotoxicity at high dosages but demonstrated immunomodulatory effects at low dosages as suppression of Treg cells and enhanced IFN- γ + tumor-specific T cell responses were able to delay tumor progression [ 120 ]. Thus, the combination of low-dose cyclophosphamide with peptide-based cancer vaccines could provide clinical benefits since cyclophosphamide could selectively deplete Tregs and modulate dendritic cell homeostasis [ 121 , 122 ]. A phase I clinical trial of RNF43 peptide-pulsed DCs combined with low-dose cyclophosphamide and IL-2 was shown to be safe.…”