Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition

Abstract

Background: Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy.

Case presentation: We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab.

Conclusion: Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy.

Keywords: Anti-CTLA4; Anti-PD1; Brain metastases; Checkpoint inhibitors; Ipilimumab; Melanoma; Nivolumab; Pembrolizumab; T-Vec; Talimogene laherparepvec.

Fig. 1

CNS response following radiotherapy and immunotherapy. a CNS lesions following gamma knife surgery (GKS), prior to whole brain radiation therapy (WBRT) and Talimogene laherparepvec (T-Vec). b Three months post WBRT and initiation of T-Vec (c) Six months following T-Vec

Fig. 2

Timeline of the patient’s clinical course. GKS = Gamma knife surgery, WBRT = Whole brain radiotherapy. Ipi/Nivo = Concurrent ipilimumab and nivolumab

Fig. 3

Representative tissue analysis using Quantitative Multiplex Immunofluorescence (qmIF). a 4 μm tissue section slide is processed using sequential qmIF protocol which uses tyrosine signal amplification following application of secondary antibody. After tissue processing, multispectral tissue images are obtained. b Cellular phenotyping is performed using companion software (inForm) which uses machine learning to perform automated cell phenotyping based on representative cell selection producing a Cartesian map with the X,Y coordinates of each cell in the imaged tissue, along with its assigned phenotype. c Spatial analysis can be performed using a variety of approaches including nearest neighbor calculation. As an example, distance between tumor cells (SOX10+) and nearest neighboring CTL (CD3 + CD8+) is being depicted

Fig. 4

Cellular phenotyping of the tumor immune microenvironment (TME). a T Cell infiltration – Total CD3 vs. CTL infiltration in tumor (dark) and stroma (light) (b) Cytotoxic T cell (CTL) activation by tissue location and activation status, HLADR+ active/HLA-DR- inactive. c CD68 distribution by location. d SOX10+ PDL1 expression. Of note, representative tissue images did not include any PDL1+ CD68 cells or PDL1+ tumor (SOX10+) cells