31 research outputs found
Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors
Checkpoint inhibitors have improved the survival of patients with advanced tumors and show
a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of
a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery,
external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with
Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation
between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and
abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and
a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic
evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial
lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in
a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment
with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade
1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient
experienced a major partial response and, following the resolution of diarrhea, she was re-challenged
again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be
considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy
shows macroscopically normal colonic mucosa inflammatory lesions
Endoscopical and pathological dissociation in severe colitis induced by immune-checkpoint inhibitors
Checkpoint inhibitors have improved the survival of patients with advanced tumors and show
a manageable toxicity profile. However, auto-immune colitis remains a relevant side effect, and combinations of anti-PD1/PDL1 and anti-CTLA-4 increase its incidence and severity. Here, we report the case of
a 50-year-old patient diagnosed with stage IV cervical cancer that relapsed following radical surgery,
external radiation/brachytherapy and standard chemotherapy. She was subsequently treated with
Nivolumab and Ipilimumab combination and developed grade 2 colitis presenting a dissociation
between endoscopic and pathological findings. At cycle 10 the patient reported grade 3 diarrhea and
abdominal discomfort, without blood or mucus in the stools. Immunotherapy was withheld and
a colonoscopy was performed, showing normal mucosa in the entire colon. Puzzlingly, histologic
evaluation of randomly sampled mucosal biopsy of the distal colon showed an intense intraepithelial
lymphocyte infiltration with crypt loss and some regenerating crypts with a few apoptotic bodies set in
a chronically inflamed lamina propria, consistent with the microscopic diagnosis of colitis. Treatment
with methylprednisolone 2 mg/kg was initiated which led to a decrease in the number of stools to grade
1. Additional investigations to exclude other causes of diarrhea rendered negative results. The patient
experienced a major partial response and, following the resolution of diarrhea, she was re-challenged
again with immunotherapy, with the reappearance of grade 2 diarrhea, leading to permanent immunotherapy interruption. We conclude and propose that performing random colonic biopsies should be
considered in cases of immune checkpoint-associated unexplained diarrhea, even when colonoscopy
shows macroscopically normal colonic mucosa inflammatory lesions
Combined immunotherapy encompassing intratumoral poly-ICLC, dendritic-cell vaccination and radiotherapy in advanced cancer patients
Background: Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local
injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows
efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal
effects.
Patients and methods: In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four
intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with
poly-ICLC (Hiltonol), TNF-a and IFN-a. On days Ăľ8 and Ăľ10 of each cycle, patients received intratumoral image-guided 0.25 mg
injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients
received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression
of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs)
and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and posttreatment PBMC from patients achieving durable stable disease (SD) were studied by IFNc ELISPOT-assays responding to
tumor-lysate loaded DC and by TCRb sequencing.
Results: Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient
experienced a remarkable mixed abscopal response to SABRĂľ immunotherapy. No objective responses were observed, while
nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-b and IFN-a
mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1b concentrations, especially in patients presenting SD.
IFNc-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.
Conclusions: This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in
combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary
clinical efficacy