Abstract P073: Gut microbiota shift in melanoma patients undergoing immunotherapy is associated with clinical response

Abstract Background Most metastatic melanoma patients treated with Programed cell Death (PD)-1 blockers fail to achieve a durable response. The gut microbiota profoundly affects host immunity, and fecal microbiota transplantations (FMT) have been shown to enhance anti-PD-1 effectiveness in murine models. We report initial safety and efficacy results from the first patients treated in a Phase I study of FMT and re-induction anti-PD-1 therapy in anti-PD-1 refractory metastatic melanoma. Methods FMT donors were two metastatic melanoma patients who achieved a durable complete response to treatment. FMT recipients were metastatic melanoma patients who failed at least one anti-PD-1 line of treatment. FMT was conducted by both colonoscopic and oral administration, followed by anti-PD-1 re-treatment. Each recipient underwent pre- and post-treatment stool sampling, tissue biopsy of both gut and tumor, and total body imaging. Results Five patients with treatment-resistant metastatic melanoma were recruited. No FMT-related or immunotherapy-related adverse events were observed. To assess engraftment of the new microbiota, recipients were paired with their respective donors and stool 16S rDNA gene sequence analysis was performed. Sequencing results demonstrated post-FMT compositional dissimilarity (Unweighted UniFrac, P = 0.04, FDR q = 0.22) between the two recipient–donor groups. Specific taxonomic dynamics included post-FMT increased abundance of Paraprevotellaceae, previously associated in descriptive studies with responsiveness to treatment, and significant reductions in abundance of β-proteobacteria, previously associated with reduced response to treatment. Immunohistochemical stains of biopsies demonstrated an increased post-FMT infiltration of antigen presenting cells (CD68+) in the gut (paired T-test, P = 0.008) and in the tumor (P = 0.0076). Post-treatment intra-tumoral CD8+ T-cell infiltration was also increased. Three patients had a partial or complete response to treatment post-FMT. Conclusion FMT in metastatic melanoma patients seems to be safe and may alter recipient gut microbiota to resemble that of a responder donor. This alteration may result in intra-tumoral T-cell activity, and conferred clinical and radiological benefit in several recipients previously unresponsive to treatment. Disclosures All Authors: No reported Disclosures.

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IN VITRO PREDICTORS OF CLINICAL RESPONSE IN MELANOMA PATIENTS RECEIVING TUMOR INFILTRATING LYMPHOCYTE (TIL) IMMUNOTHERAPY

Journal of Immunotherapy ◽

10.1097/00002371-199311000-00060 ◽

1993 ◽

Vol 14 (4) ◽

pp. 368

Author(s):

D J Schwartzentruber ◽

S S Hom ◽

R D Daneshvar ◽

J R Yannelli ◽

S M Steinberg ◽

...

Keyword(s):

Clinical Response ◽

Tumor Infiltrating Lymphocyte ◽

Melanoma Patients

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The proportion of circulating CD45RO + CD8 + memory T cells is correlated with clinical response in melanoma patients treated with ipilimumab

European Journal of Cancer ◽

10.1016/j.ejca.2016.12.031 ◽

2017 ◽

Vol 75 ◽

pp. 268-279 ◽

Cited By ~ 26

Author(s):

Julia K. Tietze ◽

Daniela Angelova ◽

Markus V. Heppt ◽

Markus Reinholz ◽

William J. Murphy ◽

...

Keyword(s):

T Cells ◽

Clinical Response ◽

Memory T Cells ◽

Melanoma Patients ◽

Cd8 Memory T Cells

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Ipilimumab reshapes T cell memory subsets in melanoma patients with clinical response

OncoImmunology ◽

10.1080/2162402x.2015.1136045 ◽

2016 ◽

Vol 5 (7) ◽

pp. 1136045 ◽

Cited By ~ 12

Author(s):

Joana Felix ◽

Jérome Lambert ◽

Marie Roelens ◽

Eve Maubec ◽

Hélène Guermouche ◽

...

Keyword(s):

T Cell ◽

Clinical Response ◽

T Cell Memory ◽

Cell Memory ◽

Melanoma Patients

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Phase I-II open label multicenter study of PD0332991 in BRAFV600mut metastatic melanoma patients harboring CDKN2A loss and RB1 expression and treated with vemurafenib.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9545 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9545-9545

Author(s):

Baptiste Louveau ◽

Matthieu Resche-Rigon ◽

Thierry Lesimple ◽

Marc Pracht ◽

Barouyr Baroudjian ◽

...

Keyword(s):

Cell Cycle ◽

Phase I ◽

Clinical Response ◽

Metastatic Melanoma ◽

Maximum Tolerated Dose ◽

Fixed Dose ◽

Open Label ◽

Melanoma Patients ◽

Group 2 ◽

Group 1

9545 Background: Among mechanisms of resistance to BRAF inhibitors (BRAFi), cell cycle effectors including CDK4 have been involved in ERK reactivation. In this phase I-II open label study, we aimed to establish the Maximum Tolerated Dose (MTD) of PD0332991, an inhibitor of CDK4/6, when added to vemurafenib (VM) in metastatic melanoma patients. Methods: Patients with BRAFV600E/K mutated metastatic melanoma harbouring CDKN2A loss and RB1 expression were included. Patients were treated with a 14 days followed by 7 days rest daily dosing schedule of PD0332991 + continuous BID dosing of VM, and stratified into 2 groups according to previous BRAFi treatment (no group 1, yes group 2). Dose levels (PD0332991 (mg/QD)/VM (mg/BID) ranged from 25/720 to 200/960. The primary endpoint was the occurrence of a DLT within the first 2 cycles of therapy. Secondary endpoints included best response (RECIST), OS, PFS, pharmacokinetics parameters, tumour molecular profiling on baseline lesions using transcriptomic and NGS analysis. Results: Nineteen patients were enrolled, among them 16 (84%) in group 2, with 18.5 months median follow-up. Characteristics at baseline were: male 11 (58%), median age 54.4 years, unresectable stage IIIC 2 (11%), stage IV 17 (89%), M1C 12 (67%), high LDH 9 (47%), median time from advanced melanoma diagnosis to inclusion 26.8 months, ≥ 2 lines therapy 13 (68%). A DLT was observed for 1 and 5 patients in group 1 and 2 respectively, defining the MTD at PD0332991 25mg and VM 960mg in group 2. No significant evidence for drug-drug interaction between PD0332991 and VM was highlighted. In group 2, ORR was estimated to 4 (25%), SD to 8 (50%), median PFS to 9.3 months and median OS to 13.2 months. Baseline transcriptomic analysis revealed high alteration rate associated with clinical response and enrichment in genes related to MAPK, cell cycle and apoptosis pathways. Conclusions: While combination of fixed dose of PD0332991 + VM did not allow us to increase PD0332991 dosage above 25mg, significant clinical benefit was achieved in heavily pretreated patients; baseline molecular analysis revealed an association between transcriptomic data and clinical response. Clinical trial information: NCT02202200.

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