Targeted therapy in melanoma

Malignant melanoma is a highly lethal disease unless detected early. Single-agent chemotherapy is well tolerated but is associated with very low response rates. Combination chemotherapy and biochemotherapy may improve objective response rates but do not prolong survival and are associated with greater toxicity. Immunotherapeutic approaches such as high-dose interleukin-2 are associated with durable responses in a small percentage of patients, but are impractical for many patients due to accessibility and toxicity issues. Elucidations of the molecular mechanisms of carcinogenesis in melanoma have expanded the horizon of opportunity to alter the natural history of the disease. Multiple signal transduction pathways seem to be aberrant and drugs that target them have been and continue to be in development. In this review we present data on the most promising targeted agents in development, including B-raf inhibitors and other signal transduction inhibitors, oligonucleotides, proteasome inhibitors, as well as inhibitors of angiogenesis. Most agents are in early phase trials although some have already reached phase III evaluation. As knowledge and experience with targeted therapy advance, new challenges appear to be arising particularly in terms of resistance and appropriate patient selection

The Epigenetic Regulation of Chemotherapy Resistance in Melanoma

Melanoma is rapidly increasing in incidence throughout the world. Early stages are curable with surgical approaches with excellent prognosis. However, a substantial proportion of patients progress to metastatic disease with survival rates of less than 5% making melanoma the culprit for over 65% of all skin-cancer related deaths. Novel agents targeting the immune system and the signaling pathways of melanoma are generating new promise, but chemotherapy remains an important therapeutic alternative, despite low response rates. The resistance of melanoma to chemotherapy is in part due to DNA repair mechanisms that allow cells to survive alkylation damage. Several novel agents targeting the abrogation of DNA repair pathways alone and in combination with cytotoxic agents have been developed with varying measures of success. In this dissertation, we first identified the epigenetic silencing of the DNA mismatch repair (MMR) gene MLH1 as a determinant of response and survival for melanoma patients treated with alkylator-based chemotherapy (dacarbazine/ temozolomide). We then determined the safe dosage of the epigenetic agent decitabine that can be administered in combination with temozolomide. The safety, tolerability and efficacy of the combination of decitabine and temozolomide were evaluated in a Phase II population. We finally determined the pharmacokinetic and pharmacodynamic effects of treatment with the combination of decitabine and temozolomide in the blood and tumor tissues of metastatic melanoma patients

Chordoma: The Nonsarcoma Primary Bone Tumor

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139965/1/onco1344.pd

Epidermal Growth Factor Receptor Expression and Mutational Analysis in Synovial Sarcomas and Malignant Peripheral Nerve Sheath Tumors

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140003/1/onco0459.pd

CD8+ T cell responses in metastatic melanoma patients receiving an adenovirally antigen engineered dendritic cell vaccine +/- IFN-α

Dendritic cells (DC), the primary antigen presenting cells and stimulators of naïve immune cells, are uniquely positioned to promote anti-tumor immunity. We developed a DC vaccine which expresses three full length melanoma antigens tyrosinase, MART-1, and MAGE-A6 engineered with an Ad type 5 adenovirus “AdVTMM2” which can activate CD8+ and CD4+ T cells as well as natural killer (NK) cells. A clinical trial testing this vaccine as well as the potential effects of IFN-α administration post-vaccination has enrolled 36 patients to date (NCT01366144). Peripheral blood banked at baseline, post-DC vaccination, and after either observation or one month of high dose IFN-α was tested for anti-tumor immunity. Here, we present initial immune response testing of the 12 HLA-A2+ patients who were able to be assessed for circulating CD8+ T cell frequencies by HLA-A2-peptide dextramers. Patient PBMCs were analyzed by MHC dextramer binding assay to determine 1) the frequency of CD8+ cells specific to vaccine encoded antigens in the subset of HLA-A2+ patients and 2) potential determinant spreading to antigens not in the vaccine, 3) frequency and co-expression of the checkpoint inhibitor molecules CTLA-4, PD-1, and TIM-3 on CD8+ T cells, and 4) to characterize three NK cell subpopulations. On the CD8+ T cells, PD-1 was the checkpoint molecule most commonly expressed, while CTLA-4 was minimally expressed. TIM-3 was the checkpoint molecule most commonly expressed on all three subpopulations of NK cells. We observed that most patients developed vaccine-encoded antigen-specific responses, and a subset demonstrated determinant spreading to non-vaccine encoded antigens gp100 and/or NY-ESO-1. Expression of checkpoint molecules changed on both T and NK cells through the treatment periods, and the function (by IFNγ ELISPOT) was also assessed. This study will aid in the design of more effective dendritic cell vaccines and adjuvants for metastatic melanoma patients

Physician Views On the Provision of information On Immune Checkpoint inhibitor therapy to Patients With Cancer and Pre-Existing autoimmune Disease: a Qualitative Study

Immune checkpoint inhibitors (ICIs) have improved cancer outcomes but can cause severe immune-related adverse events (irAEs) and flares of autoimmune conditions in cancer patients with pre-existing autoimmune disease. The objective of this study was to identify the information physicians perceived as most useful for these patients when discussing treatment initiation with ICIs. Twenty physicians at a cancer institution with experience in the treatment of irAEs were interviewed. Qualitative thematic analysis was performed to organize and interpret data. The physicians were 11 medical oncologists and 9 non-oncology specialists. The following themes were identified: (1) current methods used by physicians to provide information to patients and delivery options; (2) factors to make decisions about whether or not to start ICIs in patients who have cancer and pre-existing autoimmune conditions; (3) learning points for patients to understand; (4) preferences for the delivery of ICI information; and (5) barriers to the implementation of ICI information in clinics. Regarding points to discuss with patients, physicians agreed that the benefits of ICIs, the probability of irAEs, and risks of underlying autoimmune condition flares with the use of ICIs were most important. Non-oncologists were additionally concerned about how ICIs affect the autoimmune disease (e.g., impact on disease activity, need for changes in medications for the autoimmune disease, and monitoring of autoimmune conditions)

Society for Immunotherapy of Cancer (SITC) consensus definitions for resistance to combinations of immune checkpoint inhibitors with chemotherapy

Although immunotherapy can offer profound clinical benefit for patients with a variety of difficult-to-treat cancers, many tumors either do not respond to upfront treatment with immune checkpoint inhibitors (ICIs) or progressive/recurrent disease occurs after an interval of initial control. Improved response rates have been demonstrated with the addition of ICIs to cytotoxic therapies, leading to approvals from the US Food and Drug Administration and regulatory agencies in other countries for ICI-chemotherapy combinations in a number of solid tumor indications, including breast, head and neck, gastric, and lung cancer. Designing trials for patients with tumors that do not respond or stop responding to treatment with immunotherapy combinations, however, is challenging without uniform definitions of resistance. Previously, the Society for Immunotherapy of Cancer (SITC) published consensus definitions for resistance to single-agent anti-programmed cell death protein 1 (PD-1). To provide guidance for clinical trial design and to support analyses of emerging molecular and cellular data surrounding mechanisms of resistance to ICI-based combinations, SITC convened a follow-up workshop in 2021 to develop consensus definitions for resistance to multiagent ICI combinations. This manuscript reports the consensus clinical definitions for combinations of ICIs and chemotherapies. Definitions for resistance to ICIs in combination with targeted therapies and with other ICIs will be published in companion volumes to this paper

Retrospective Determination of Prognostic Factors in BRAF-V600E Melanoma Brain Metastases​

View full abstracthttps://openworks.mdanderson.org/leading-edge/1030/thumbnail.jp

Spartalizumab or placebo in combination with dabrafenib and trametinib in patients with BRAF\textit{BRAF}V600-mutant melanoma: exploratory biomarker analyses from a randomized phase 3 trial (COMBI-i)

BackgroundThe randomized phase 3 COMBI-i trial did not meet its primary endpoint of improved progression-free survival (PFS) with spartalizumab plus dabrafenib and trametinib (sparta-DabTram) vs placebo plus dabrafenib and trametinib (placebo-DabTram) in the overall population of patients with unresectable/metastatic $\textit{BRAF}$V600-mutant melanoma. This prespecified exploratory biomarker analysis was performed to identify subgroups that may derive greater treatment benefit from sparta-DabTram.MethodsIn COMBI-i (ClinicalTrials.gov, NCT02967692), 532 patients received spartalizumab 400 mg intravenously every 4 weeks plus dabrafenib 150 mg orally two times daily and trametinib 2 mg orally one time daily or placebo-DabTram. Baseline/on-treatment pharmacodynamic markers were assessed via flow cytometry-based immunophenotyping and plasma cytokine profiling. Baseline programmed death ligand 1 (PD-L1) status and T-cell phenotype were assessed via immunohistochemistry; $\textit{BRAF}$V600 mutation type, tumor mutational burden (TMB), and circulating tumor DNA (ctDNA) via DNA sequencing; gene expression signatures via RNA sequencing; and CD4$^{+}$/CD8$^{+}$ T-cell ratio via immunophenotyping.ResultsExtensive biomarker analyses were possible in approximately 64% to 90% of the intention-to-treat population, depending on sample availability and assay. Subgroups based on PD-L1 status/TMB or T-cell inflammation did not show significant differences in PFS benefit with sparta-DabTram vs placebo-DabTram, although T-cell inflammation was prognostic across treatment arms. Subgroups defined by $\textit{BRAF}$V600K mutation (HR 0.45 (95% CI 0.21 to 0.99)), detectable ctDNA shedding (HR 0.75 (95% CI 0.58 to 0.96)), or CD4$^{+}$/CD8$^{+}$ ratio above median (HR 0.58 (95% CI 0.40 to 0.84)) derived greater PFS benefit with sparta-DabTram vs placebo-DabTram. In a multivariate analysis, ctDNA emerged as strongly prognostic (p=0.007), while its predictive trend did not reach significance; in contrast, CD4$^{+}$/CD8$^{+}$ ratio was strongly predictive (interaction p=0.0131).ConclusionsThese results support the feasibility of large-scale comprehensive biomarker analyses in the context of a global phase 3 study. T-cell inflammation was prognostic but not predictive of sparta-DabTram benefit, as patients with high T-cell inflammation already benefit from targeted therapy alone. Baseline ctDNA shedding also emerged as a strong independent prognostic variable, with predictive trends consistent with established measures of disease burden such as lactate dehydrogenase levels. CD4$^{+}$/CD8$^{+}$ T-cell ratio was significantly predictive of PFS benefit with sparta-DabTram but requires further validation as a biomarker in melanoma. Taken together with previous observations, further study of checkpoint inhibitor plus targeted therapy combination in patients with higher disease burden may be warranted

The Great Debate at \u27Immunotherapy Bridge\u27, Naples, December 5, 2019.

As part of the 2019 Immunotherapy Bridge congress (December 4-5, Naples, Italy), the Great Debate session featured counterpoint views from leading experts on six topical issues in immunotherapy today. These were the use of chimeric antigen receptor T cell therapy in solid tumors, whether the Immunoscore should be more widely used in clinical practice, whether antibody-dependent cellular cytotoxicity is important in the mode of action of anticytotoxic T-lymphocyte-associated protein 4 antibodies, whether the brain is immunologically unique or just another organ, the role of microbiome versus nutrition in affecting responses to immunotherapy, and whether chemotherapy is immunostimulatory or immunosuppressive. Discussion of these important topics are summarized in this report