Patient case: 34-year-old female with melanoma; genetic feature: NRAS (Q61L)

Clinical trial: Understanding Immunotherapy Resistance Mechanisms in Advanced Melanoma

Summary: Purpose of the study:
  The investigators are proposing that melanomas which respond and develop eventual disease stability in response to checkpoint inhibitor immunotherapy undergo a genetic program promoting secondary resistance.

Detailed description: Understanding these genetic alterations and the factors which contribute to this process would be critical for the identification of novel immunotherapeutic targets which may synergize with the T cell-targeted checkpoint inhibitors. Furthermore, this work promises to provide greater insight into tumor-mediated immune evasion mechanisms and primary immunotherapy resistance, potentially unveiling predictive markers of clinical response for our expanding arsenal of immune checkpoint inhibitor therapies.
  Many patients who exhibit a response to the anti-PD-1 antibodies develop a prolonged course of disease stability which resembles the equilibrium phase of the previously proposed process of cancer immunoediting. This state of equipoise has been hypothesized to involve genetic alterations that promote immune evasion and, in some cases, lead to the development of tumor escape. Based on our data, the investigators propose that melanomas that develop a period of disease stability in response to anti-PD-1 immunotherapy exhibit genetic alterations that suppress the effectiveness of anti-tumor immunity. Our previous studies indicate that the tumor-derived factors that play a role in the paracrine signaling pathways capable of regulating nearby stromal cell populations are more likely to be critical immune regulators of the tumor microenvironment. Therefore, the investigators will focus our studies on those differentially expressed genes which encode soluble proteins using an available prediction algorithm. Those genes identified by this study to be differentially expressed in the melanoma tissues of patients demonstrating a clinical response to immune checkpoint inhibitor therapy will be further evaluated in transgenic autochthonous melanoma models.

Eligibility: Inclusion Criteria
  -  Patients with unresectable stage IIIC or IV melanoma, with melanoma validated by histology or cytology
  -  Patients may participate with primary cutaneous melanomas of unknown primary site, primary mucosal melanomas, or ocular melanomas
  -  Age ≥ 18 years
  -  ECOG performance status of 0-2
  -  Life expectancy of at least 6 months
  -  Patient will be treated with either anti-CTLA-4 antibody or anti-PD-1 antibody therapy
  -  Melanoma lesion accessible for tissue biopsy defined as a superficial skin lesion or a deeper soft-tissue lesion felt to be of minimal risk for an image-guided biopsy. This includes superficial hepatic lesions but does not include pulmonary nodules or deep hepatic lesions near critical anatomic structures. Each patient will be individually discussed by a physician panel comprised of the study PI, a study sub-investigator, and an independent interventional radiologist prior to enrollment.
  -  Both men and women of all races and ethnic groups are eligible for this trial.
  -  Ability to understand and the willingness to sign a written informed consent document
  -  Patients with intra-cranial disease or disease involving the central nervous system are eligible
  -  Patient has normal marrow function and organ function as defined below:
  -  Leukocytes ≥3,000/mcL
  -  Absolute neutrophil count ≥1,000/mcL
  -  Platelets ≥75,000/mcL
  -  Hemoglobin >9 g/dL
  -  Total bilirubin <1.5 × institutional upper limit of normal [bilirubin < 3 × institutional upper limit of normal for Gilbert's syndrome]
  -  AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal
  -  Creatinine < 1.5 x institutional upper limit of normal OR Creatinine clearance ≥ 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
  Exclusion Criteria
  -  Patients with a history of a systemic autoimmune disease (eg systemic lupus erythematosus) requiring active therapy
  -  Patients who have had prior cytotoxic chemotherapy.
  -  Patients who have had prior interferon therapy if less than 4 weeks prior to day of initial biopsy
  -  Patients who have had prior anti-CTLA-4 antibody or anti-PD-1 antibody therapy if less than 4 weeks prior to day of initial biopsy
  -  Patients who have had prior IL-2 therapy if less than 4 weeks prior to day of initial biopsy
  -  Patients who are undergoing active steroid therapy at any dose
  -  Patients with a history of an immunodeficiency disorder including HIV
  -  Patients with ongoing or active infection that provider feels is clinically significant
  -  Pregnant patients

Relevance to patient case: not relevant