Jade Homsi

Specific lymphocyte subsets predict response to adoptive cell therapy using expanded autologous tumor-infiltrating lymphocytes in metastatic melanoma patients.

Purpose: Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) is a promising treatment for metastatic melanoma unresponsive to conventional therapies. We report here on the results of an ongoing phase II clinical trial testing the efficacy of ACT using TIL in patients with metastatic melanoma and the association of specific patient clinical characteristics and the phenotypic attributes of the infused TIL with clinical response. Experimental Design: Altogether, 31 transiently lymphodepleted patients were treated with their expanded TIL, followed by two cycles of high-dose interleukin (IL)-2 therapy. The effects of patient clinical features and the phenotypes of the T cells infused on the clinical response were determined. Results: Overall, 15 of 31 (48.4%) patients had an objective clinical response using immune-related response criteria (irRC) with 2 patients (6.5%) having a complete response. Progression-free survival of more than 12 months was observed for 9 of 15 (60%) of the responding patients. Factors significantly associated with the objective tumor regression included a higher number of TIL infused, a higher proportion of CD8+ T cells in the infusion product, a more differentiated effector phenotype of the CD8+ population, and a higher frequency of CD8+ T cells coexpressing the negative costimulation molecule “B- and T-lymphocyte attenuator” (BTLA). No significant difference in the telomere lengths of TIL between responders and nonresponders was identified. Conclusion: These results indicate that the immunotherapy with expanded autologous TIL is capable of achieving durable clinical responses in patients with metastatic melanoma and that CD8+ T cells in the infused TIL, particularly differentiated effectors cells and cells expressing BTLA, are associated with tumor regression. Clin Cancer Res; 18(24); 6758–70. ©2012 AACR.

Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors.

BACKGROUND Angiogenesis plays an important role in tumor growth and metastasis. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Methylphenidate for fatigue in advanced cancer: a prospective open-label pilot study.

Psychostimulants such as methylphenidate are used for fatigue in cancer patients. We report a prospective, open-label, pilot study of the successful use of methylphenidate to treat fatigue in nine of 11 consecutive patients with advanced cancer. Seven had received radiation or chemotherapy, a median of three weeks (range from one to 30 weeks) prior to methylphenidate. A rapid onset of benefit was noted, even in the presence of mild anemia. Sedation and pain also improved in some. Only one patient had side effects severe enough to stop the medication.

A phase II study of methylphenidate for depression in advanced cancer

This study evaluated the use of methylphenidate for depression in advanced cancer. Design: Phase II open-label prospective study. Eligibility criteria: No previous use of methylphenidate or current use of other antidepressants. Evaluation: Depression and response to treatment were determined by asking the patient: “are you depressed?” Patients were assessed at baseline and at days 3, 5, and 7. Treatment: Starting dose was 5 mg at 8:00 a.m. and 12:00 noon. The dose was titrated for lack of response on any of the assessment days. Response criteria: A negative response to the question: “are you depressed?” Results: Some 41 patients were enrolled and 30 (15 men, 15 women) completed the study. Median age was 68 years (range: 30-90). Methylphenidate was stopped for six patients because of side effects and five were not evaluable; 21 responded to 10 mg/day on day 3; the other nine responded to 20 mg/day on day 5; 29 maintained their positive response through day 7. Anorexia, fatigue, concentration, and sedation also improved in some. All who completed the study had tolerable side effects, none of which caused treatment to stop. Conclusions: Methylphenidate is effective for depression in advanced cancer. A starting dose of 10 mg in divided doses is effective in most patients. Dose escalation may be needed. Improvement occurs within three days. Close monitoring of side effects is recommended.

Cutaneous Melanoma: Prognostic Factors

BACKGROUND Recent data have changed our views of prognostic factors in cutaneous melanoma. While some newer methods have yielded better prognostic information, some insights have evolved as a result of large-scale population-based analyses. METHODS We review current data on several different prognostic factors and divide these factors according to their application in localized primary melanoma or metastatic melanoma. For each prognostic factor, the level of evidence supporting its use and its applicability to clinical practice are considered. RESULTS For localized primary melanoma, the dominant predictors of survival include lesion thickness, ulceration, and lymph node involvement. Factors such as age, sex, anatomic location, and satellite/in-transit lesions are important in localized melanoma. Factors currently being investigated are tumor vascularity, vascular invasion, mitotic rate, tumor regression, and tumor-infiltrating lymphocytes. For metastatic melanoma, the most important prognostic factors are site of metastases and the presence of elevated serum lactic dehydrogenase. The value of these prognostic factors to clinicians caring for melanoma patients is discussed. CONCLUSIONS A better understanding of prognostic factors in cutaneous melanoma has evolved over the last decade, allowing oncologists to provide appropriate treatment for their patients. Many of the prognostic factors are interrelated. In the near future, it is expected that several molecular genetic factors will provide more insight into the prognosis of patients with melanoma.

Phase I Trial of Poly-l-Glutamate Camptothecin (CT-2106) Administered Weekly in Patients with Advanced Solid Malignancies

Purpose: CT-2106 is a 20(S)-camptothecin poly-l-glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-l-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies. Experimental Design: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high-performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively. Results: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 mg/m2 given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t1/2 range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively. Conclusions: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 mg/m2 weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.

A Phase IB Trial of Intravenous INO-1001 Plus Oral Temozolomide in Subjects with Unresectable Stage-III or IV Melanoma

INO-1001 is a PARP-1 inhibitor that interrupts the repair process of N-methylpurines generated by temozolomide. We evaluated the pharmacokinetics of INO-1001 and determined its safety when used with temozolomide at 200 mg/m2/day × 5 days every 4 weeks. We enrolled 12 adult patients, in cohorts of 3–6 patients, into the study. INO-1001 at doses of 100, 200 and 400 mg was given intravenous for 1 hr q 12 hr for 10 doses. INO-1001 had a moderate clearance, volume of distribution and a relatively short terminal half-life. Myelosuppression and elevation of liver transaminases were dose-limiting toxicities (DLTs) of INO-1001 at 400 mg.

The Src signaling pathway: a potential target in melanoma and other malignancies

Although Src was the first oncogene to be discovered as the transforming protein of the Rous sarcoma virus almost three decades ago, the role of Src and the Src family kinases in human oncogenesis is still not completely understood. Recent studies have shown that Src regulates cell adhesion, invasiveness and motility in cancer cells and in tumor vasculature, rather than directly influencing cell replication. The role of the Src family kinases in human cancer is evolving and elevated levels of Src kinase activity have been reported in a number of human cancers in vitro and in vivo. Src expression and activity are increased in melanoma cell lines and in melanoma tumors in vivo. Src can activate STAT3, STAT5 and other downstream targets in melanoma. Src and STAT3 are expressed in their activated forms in both primary and metastatic melanoma in humans, although the expression level is variable. Cumulatively, these data mark Src signaling as attractive therapeutic targets in melanoma. Studies are currently underway with novel Src inhibitors in melanoma and in other tumor types.

Psychostimulants in supportive care.

Abstract Psychostimulant medications have been used clinically and investigated in psychiatric populations, the medically ill, cancer patients and healthy people. This article discusses the pharmacology of dextroamphetamine, methylphenidate, pemoline (and other psychostimulants such as caffeine and ephedrine), their use in general medicine and cancer care, side effects, and abuse potential. Therapeutic use in children is addressed only insofar as it illustrates facets of their use in adults.

Symptom severity and distress in advanced cancer

We determined the relationship between symptom severity and distress for multiple cancer symptoms, and examined patient demographic influences on severity and distress in advanced cancer. A Cochran—Armitage trend test determined whether symptom distress increased with severity. Chi-square, Fisher’s exact test and logistic regression analysis examined moderate/severe (‘clinically important’) and distressful symptoms by age (≤65 versus >65), gender, primary site group, and ECOG performance status. Forty-six symptoms were analyzed in 181 individuals. More than 50% of individuals with clinically important symptoms rated them as distressful. The median percentage of individuals with mild but still distressful symptoms was 25%, with a range of 0% (bad dreams) to 73% (sore mouth). In both univariate and multivariate analysis, younger (≤65 years) patients, females, and those with poor performance status had more clinically important and a higher prevalence of distressful symptoms (only anxiety was more frequently distressful to older individuals). Clinically important symptoms and two of those considered distressful varied by primary site group. After control for severity, symptom distress did not differ by primary site group. The prevalence of distress increased with greater symptom severity. Younger individuals, those with poor performance status, and females had greater symptom severity and distress. Mild symptoms were often distressful. After adjustment for severity, age, gender, and performance status all influenced symptom distress.