Immunotherapy of melanoma: an update Homsi, Jade; Grimm, Joshua C; Hwu, Patrick
Surgical oncology clinics of North America
20, Issue:
1
Journal Article
Peer reviewed
The incidence of melanoma has been increasing worldwide. A relationship between melanoma and the immune system was established years ago. Modulating the immune system in the management of different ...stages of melanoma has been the focus of numerous large randomized trials worldwide. This article reviews the current status of immunotherapy for melanoma, with a focus on the recent promising results from using vaccines, cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibodies, and adoptive cell therapy.
The enzymes in the cytochrome p450 monooxygenase system (CYP) are the major enzymes responsible for metabolizing medications. The CYP2D6 isomer is responsible for metabolizing certain opioids, ...neuroleptics, antidepressants and cardiac medications. Owing to CYP2D6's low capacity and high affinity it is easily saturated by substrate and/or inhibited, resulting in pharmacokinetic interactions. Polymorphisms of the structural gene are common, leading to wide inter-individual and ethnic differences in drug metabolism. Clinically important drug interactions, which may be anticipated in the palliative medicine population, are reviewed.
This prospective study of consecutive patients describes the palliative medicine consult service in a tertiary level cancer center and its impact on patient care. All inpatients/outpatients referred ...to the Palliative Medicine Program in a 4-month period were enrolled. Data were collected at the initial consultation using standardized forms with spaces for: reason for the consultation, referring service, demographics and history, ECOG performance status, symptoms, prognosis and diagnostic tests, treatment, and care plan. In all, 240 patients were seen: 79% were referred for symptom management; 53% were referred from medical oncology; and 50% were women. Median patient age was 67 years (range 18-96). Median performance status was 2 (1-4). Most (84%) of the patients had cancer. The cancer sites were: lung in 26% of cases, colorectal in 8%, and breast in 7%. Inpatients accounted for 53% and outpatients, for 47% of the study population. The median number of symptoms per patient was 13 (2-30). The estimated survival was <2 weeks in 15%, 2-8 weeks in 38%, 2-6 months in 37%, and >6 months in 10%. The patients' goals were: improve symptoms for 84%, return home for 55%, and no further admissions for 5%. The support systems named by patients were: family in 89%, friends in 13%, and the community in 5%. Hospice care was discussed at the consultation with 38% of the patients, would have been inappropriate for 31%, was not discussed with 22%, and had been discussed before with 9%. In response to questions about psychosocial care, a caregiver was identified by 78%, a spokesperson by 75%, and durable power of attorney was referred to by 21%. The DNR status was discussed on consult by 57%, had already been discussed with 30%, and was not discussed with 13%. Plan of care foresaw outpatient follow-up for 40%, inpatient follow-up for 32%, and transfer to palliative medicine for 27%. In 39% of cases the consults were considered late referrals. New medications suggested were opioids for 46% of patients, antiemetics for 28%, a bowel regimen for 24%, steroids for 15%, and others for 51%. (1) Palliative medicine consultation involves common complex medical, psychological, and social problems. (2) Complex symptomatology in this population is confirmed. (3) Multiple interventions were suggested even at the initial consultation. (4) Important issues such as DNR (do not resuscitate) status, support system, treatment goals, and eligibility for hospice care had often not been addressed.
Angiogenesis plays an important role in tumor growth and metastasis.
We review the function of the vascular endothelial growth factor (VEGF) in vessel formation that is complemented by ...platelet-derived growth factor (PDGF). We also review the agents designed to target VEGF, PDGF, and/or their receptors.
VEGF plays a central role in tumor angiogenesis. It is expressed at increased levels in colorectal, liver, lung, thyroid, breast, as well as in bladder, ovary, uterine cancers, and in angiosarcomas, germ cell tumors, intracranial tumors, and others. VEGF blockade has been shown to have a direct and rapid antivascular effect in both animal and human tumors, through deprivation of tumor vascular supply and inhibition of endothelial proliferation. Overexpression of PDGFs and their receptors has also been reported in many types of cancers such as prostate, ovarian, and non-small-cell lung cancer. Many VEGF and PDGF inhibitors are available. The use of some of these inhibitors has significantly improved the survival of cancer patients. Several agents are in development and currently are being tested in clinical trials.
Angiogenic agents inhibiting VEGF and PDGF have shown promising clinical results. Targeting more than one pathway by combining different agents may increase the antitumor activity of these drugs. The implementation of reliable radiologic and pathologic angiogenesis monitoring techniques is necessary to implement antiangiogenic therapies in cancer.
Summary Background We previously reported rates of pathological complete responses (51% 95% CI 39−62 per independent central review, the primary endpoint) and major pathological responses (13% per ...independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. Methods This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II–IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. Findings Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66–81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6–22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79–94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82–97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83–96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one 6% cardiomyopathy and one 6% hypophysitis). There were no grade 4 adverse events or treatment-related deaths. Interpretation For patients with resectable stage II–IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. Funding Regeneron Pharmaceuticals and Sanofi.
The existing T cell-centered immune checkpoint blockade therapies have been successful in treating some but not all patients with cancer. Immunosuppressive myeloid cells, including myeloid-derived ...suppressor cells (MDSC), that inhibit antitumor immunity and support multiple steps of tumor development are recognized as one of the major obstacles in cancer treatment. Leukocyte Ig-like receptor subfamily B3 (LILRB3), an immune inhibitory receptor containing tyrosine-based inhibitory motifs (ITIM), is expressed solely on myeloid cells. However, it is unknown whether LILRB3 is a critical checkpoint receptor in regulating the activity of immunosuppressive myeloid cells, and whether LILRB3 signaling can be blocked to activate the immune system to treat solid tumors. Here, we report that galectin-4 and galectin-7 induce activation of LILRB3 and that LILRB3 is functionally expressed on immunosuppressive myeloid cells. In some samples from patients with solid cancers, blockade of LILRB3 signaling by an antagonistic antibody inhibited the activity of immunosuppressive myeloid cells. Anti-LILRB3 also impeded tumor development in myeloid-specific LILRB3 transgenic mice through a T cell-dependent manner. LILRB3 blockade may prove to be a novel approach for immunotherapy of solid cancers.
Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation ...and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m
2
orally days 1–4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.
Anal melanoma is an uncommon and aggressive cancer. Different surgical modalities have been used in managing the disease with no clear evidence to favor one approach over another.
The medical records ...of patients with anal melanoma treated at the H. Lee Moffitt Cancer and Research Institute between 1987 and 2004 were reviewed. Published anal melanoma studies, including more than ten patients with outcome data, also were reviewed.
Twelve patients were identified (8 percent of all cancer of the anal canal). Nine were females with a median age of 67 (range, 27-86) years. Four patients had nodal involvement, and one had bone metastases at the time of diagnosis. Five patients had abdominoperineal resection, and six had local excision. Adjuvant radiation therapy with or without interferon was used. Five of the 11 patients without metastatic disease relapsed or died within the first year of diagnosis (4 had local excision and 1 had abdominoperineal resection). Median time to relapse was 6.5 (range, 4-31) months. The liver was the most common site for relapse. Only one patient treated with local excision followed by interferon was a long survivor (no evidence of recurrence at 54 months).
Anorectal melanoma is a rare and challenging disease. The preoperative staging influences the treatment schedule. In the absence of strong survival benefit of abdominoperineal resection in managing the nonmetastatic form of the disease, it is reasonable to consider local excision as the initial treatment of choice. Adjuvant radiation therapy is well tolerated and is promising in improving locoregional control.
Predicting survival in patients with advanced disease is challenging for health care providers. Accurate survival estimation using symptom assessment may assist physicians and patients in determining ...treatment options. This report analyzes prospective studies in adult patients with a median/mean survival of 6 months or less and identifies symptoms that are associated with decreased survival. To be included in this analysis, a study needed to have at least one symptom associated with decreased survival in a univariate or multivariate analysis. Twenty-two studies were identified and 15 symptoms were associated with decreased survival. Anorexia, delirium, and dyspnea were associated with decreased survival in most studies. Delirium and anorexia (but not dyspnea) were associated with decreased survival in most studies that included patients with a median survival of 30 days or less. More research is needed to investigate any associations between symptom characteristics and survival in patients with advanced disease. Short assessment tools using symptoms identified in this report, with a focus on symptoms that were found in multiple studies, need to be developed to better predict survival and guide patient treatment.
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