Persistence and efficacy of second generation CAR T cell against the LeY antigen in acute myeloid leukemia.

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1.3 × 109 total T cells, of which 14-38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR-T-cell therapy in high-risk AML, and demonstrates durable in vivo persistence.

Fludarabine based combinations are highly effective as first-line or salvage treatment in patients with Waldenström macroglobulinemia.

Treatment with single-agent chemotherapy or rituximab (R) is safe and moderately effective for patients with Waldenström macroglobulinemia (WM). We analyzed the efficacy and toxicity of fludarabine (F)-combinations. Twenty-nine treatment episodes were administered to 27 patients, including FC (F 25 mg/m(2) days 1-3, cyclophosphamide [C] 250 mg/m(2) days 1-3; n = 7), FCR (FC + R 375 mg/m(2) day 1; n = 18), FM (F + mitoxantrone [M] 10 mg/m(2) day 1; n = 3), and FR (n = 1). Patient characteristics were median age 57 years (36-89), 83% male, 10 previously untreated (34%). In total, 123 cycles were administered, a median of four (2-6) per patient. Grade ≥ 3 neutropenia and infections complicated 28% and 3% of cycles, respectively. Responses were achieved in 26 cases (90%), one complete, 23 partial, and two minor. The median progression-free survival was 43.1 months, and at a median follow-up of 66.5 months the actuarial 5- and 10-year overall survival-rates were 88% and 75%, respectively. All 10 previously untreated patients responded (one CR, nine PR), and were alive at a median follow-up of 50 (6-106) months. Three heavily pretreated patients subsequently developed AML/MDS (one fatal) at 56, 61, and 91 months post F-based treatment. F-combination therapy is highly active in WM, both untreated and alkylator-refractory. However, a possible contribution to the cumulative risk of treatment-related MDS/AML requires ongoing monitoring.

Safety and efficacy of weekly 5-fluorouracil/folinic acid/oxaliplatin/irinotecan in the first-line treatment of gastrointestinal cancer.

BACKGROUND: Standard chemotherapy for patients with metastatic colorectal cancer (mCRC) or gastric cancer (GC) consists of two-drug, usually fluoropyrimidine-based, combinations, with or without the addition of biological agents. Studies of triple-drug regimens combining 5-fluorouracil (5-FU)/folinic acid (FA) with both oxaliplatin and irinotecan have shown promising efficacy in studies of patients with mCRC or GC. However, improved efficacy has often been achieved at the expense of high rates of grade 3 or 4 toxicities such as neutropenia and diarrhoea, occasionally even resulting in toxic deaths. OBJECTIVE/METHODS: We performed a phase II study of previously untreated patients with mCRC or GC to assess the safety and efficacy of our 5-fluorouracil/folinic acid/oxaliplatin/irinotecan (FUFOXIRI) regimen with weekly administration of irinotecan 70 mg/m(2), oxaliplatin 50 mg/m(2), FA 500 mg/m(2) and 5-FU 2000 mg/m(2) on days 1, 8, 15 and 22, repeated from day 36. RESULTS: A total of 22 patients were enrolled, 11 each with mCRC and GC receiving a median of four cycles per patient. The FUFOXIRI regimen was generally well tolerated with no toxic deaths, neutropenic fever or grade 4 toxicities. Most common grade 3 side effects were diarrhoea and neutropenia each affecting 24% of patients. Dose reductions due to toxicity were performed in 48% of all and 60% of patients having received at least two cycles of FUFOXIRI. The overall response rate was 46% (all partial responses), 55% and 36% for patients with mCRC and GC, respectively. Median progression-free survival for all patients, mCRC and GC patients was 9.5, 10.0 and 8.0 months, respectively. The median overall survival for all patients was 16.5, 18.0 and 15.0 months for patients with mCRC and GC, respectively. CONCLUSION: These data show excellent tolerance and efficacy of the FUFOXIRI regimen in both mCRC and GC. Therefore, FUFOXIRI is a promising backbone for future studies incorporating biologic 'targeted' agents for the treatment of gastrointestinal cancers.

The role of peri-operative treatment in resectable liver metastases of colorectal cancer.

Synchronous or metachronous colorectal liver metastases (CLMs), although being the expression of systemic disease, allow a curative approach for about 25-35% of patients. Patients presenting with CLMs should receive a multimodal management in order to increase the number of patients undergoing R0 surgery and to decrease the rate of recurrence. Postoperative and/or pre-operative systemic chemotherapy shows beneficial impact regarding progression-free and overall survival, without increasing postoperative complication rates. Concerning the complex definition of resectability and the number of patients with 'borderline' resectable CLMs, pre-operative chemotherapy plays an important role in both the improvement of prognosis and 'conversion' to resectability. Duration of chemotherapy in the peri-operative setting should not exceed 6 months. Current data do not recommend the use of locally applied chemotherapy using hepatic artery infusion after resection of CLMs. Liver surgery has made several advances extending resectability to a larger group of patients and decreasing local hepatic recurrence. Moreover, locally ablative procedures such as radiofrequency and selective internal radiation therapy have joined the armamentarium in the case of positive resection margins or unresectable disease. Future research will help in defining treatment regimens and approaches in this setting.

The Lewis-Y carbohydrate antigen is expressed by many human tumors and can serve as a target for genetically redirected T cells despite the presence of soluble antigen in serum.

In this study we aimed to determine the suitability of the Lewis-Y carbohydrate antigen as a target for immunotherapy using genetically redirected T cells. Using the 3S193 monoclonal antibody and immunohistochemistry, Lewis-Y was found to be expressed on a range of tumors including 42% squamous cell lung carcinoma, 80% lung adenocarcinoma, 25% ovarian carcinoma, and 25% colorectal adenocarcinoma. Expression levels varied from low to intense on between 1% and 90% of tumor cells. Lewis- was also found in soluble form in sera from both normal donors and cancer patients using a newly developed enzyme-linked immunosorbent assay. Serum levels in patients was often less than 1 ng/mL, similar to normal donors, but approximately 30% of patients had soluble Lewis-Y levels exceeding 1 ng/mL and up to 9 ng/mL. Lewis-Y-specific human T cells were generated by genetic modification with a chimeric receptor encoding a single-chain humanized antibody linked to the T-cell signaling molecules, T-cell receptor-zeta, and CD28. T cells responded against the Lewis-Y antigen by cytokine secretion and cytolysis in response to tumor cells. Importantly, the T-cell response was not inhibited by patient serum containing soluble Lewis-Y. This study demonstrates that Lewis-Y is expressed on a large number of tumors and Lewis-Y-specific T cells can retain antitumor function in the presence of patient serum, indicating that this antigen is a suitable target for this form of therapy.

Indolent lymphomas other than follicular and marginal zone lymphomas.

This article addresses two of the less common entities among clinically indolent B-cell non-Hodgkin lymphomas: small lymphocytic lymphoma and lymphoplasmacytic lymphoma, also known as "Waldenstrom's macroglobulinemia." Differential diagnoses and prognostic factors are discussed for each as well as new treatment options and stem cell transplantation.

Epidermal growth factor receptor tyrosine kinase inhibitors: present and future role in gastrointestinal cancer treatment: a review.

BACKGROUND: Despite advances in conventional and targeted anticancer therapy, the prognosis remains poor for many patients with solid tumors. Ongoing research into the molecular basis of malignant disease, however, has yielded many novel agents with potential activity, including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). DESIGN: This review summarizes current clinical data for EGFR-TKIs as monotherapy or in combination with 5-fluorouracil/leucovorin, irinotecan, or oxaliplatin, focusing on the rapidly developing area of colorectal, gastroesophageal, and pancreatic cancers. RESULTS: EGFR-TKIs have limited but valuable activity as monotherapy in non-small cell lung cancer patients who have received prior anticancer treatment. The potential for application as a single agent in colorectal, gastroesophageal, and pancreatic cancers has yet to be demonstrated conclusively and deserves further investigation, especially as second- or third-line therapy. In combination with oxaliplatin-based regimens and 5-fluorouracil/leucovorin-based regimens, TKIs have shown benefits, suggesting that there may be a synergistic effect with chemotherapy. However, combinations with irinotecan-based regimens have been limited by toxicities. CONCLUSIONS: EGFR-TKIs show benefits when used in combination with chemotherapy, and the favorable toxicity profiles observed suggest that these may be of value in frail or elderly patients.

Genetic protection of repopulating hematopoietic cells with an improved MDR1-retrovirus allows administration of intensified chemotherapy following stem cell transplantation in mice.

This study was undertaken to analyze the hematotoxicity of paclitaxel (Taxol) and to test whether transduction of repopulating hematopoietic cells with a retroviral vector (SF1m) expressing the human multidrug resistance 1 gene (MDR1) would permit dose intensification following bone marrow transplantation (BMT). While the regimen chosen (8 x 20 mg/kg i.p. within 12 days) produced a non-lethal, reversible hematotoxicity in mice with steady-state hematopoiesis, only 35.3% (6/17) of control mice survived when treated starting 14 days post BMT. In contrast, 83.3% (15/18) of mice transplanted with SF1m-transduced cells survived, owing to a significant protection against severe acute myelotoxicity (as determined by neutrophil counts, white and red blood cell counts and values for hemoglobin and hematocrit). After recovery from chemotherapy, an increase of myeloid cells that were resistant to colchicine and effluxed the fluorochrome Rhodamine 123 was observed in SF1m-mice, but not in controls. These results reveal that the lethal, dose-limiting hematotoxicity of an intensified post-transplantation chemotherapy with paclitaxel can be prevented by retroviral transfer of the MDR1 gene to a minor proportion of repopulating cells. Our mouse model, mimicking clinically achievable gene transfer rates, thus suggests that bone marrow chemoprotection may widen the therapeutic window and permit an earlier onset of post-transplantation chemotherapy.