[Show abstract][Hide abstract] ABSTRACT: Metastatic cervical cancer is a prototypical chemotherapy-refractory epithelial malignancy for which better treatments are needed. Adoptive T-cell therapy (ACT) is emerging as a promising cancer treatment, but its study in epithelial malignancies has been limited. This study was conducted to determine if ACT could mediate regression of metastatic cervical cancer.
Patients enrolled onto this protocol were diagnosed with metastatic cervical cancer and had previously received platinum-based chemotherapy or chemoradiotherapy. Patients were treated with a single infusion of tumor-infiltrating T cells selected when possible for human papillomavirus (HPV) E6 and E7 reactivity (HPV-TILs). Cell infusion was preceded by lymphocyte-depleting chemotherapy and was followed by administration of aldesleukin.
Three of nine patients experienced objective tumor responses (two complete responses and one partial response). The two complete responses were ongoing 22 and 15 months after treatment, respectively. One partial response was 3 months in duration. The HPV reactivity of T cells in the infusion product (as measured by interferon gamma production, enzyme-linked immunospot, and CD137 upregulation assays) correlated positively with clinical response (P = .0238 for all three assays). In addition, the frequency of HPV-reactive T cells in peripheral blood 1 month after treatment was positively associated with clinical response (P = .0238).
Durable, complete regression of metastatic cervical cancer can occur after a single infusion of HPV-TILs. Exploratory studies suggest a correlation between HPV reactivity of the infusion product and clinical response. Continued investigation of this therapy is warranted.
Published by the American Society of Clinical Oncology.
Preview · Article · Mar 2015 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Purpose:
T cells can be genetically modified to express an anti-CD19 chimeric antigen receptor (CAR). We assessed the safety and efficacy of administering autologous anti-CD19 CAR T cells to patients with advanced CD19(+) B-cell malignancies.
Patients and methods:
We treated 15 patients with advanced B-cell malignancies. Nine patients had diffuse large B-cell lymphoma (DLBCL), two had indolent lymphomas, and four had chronic lymphocytic leukemia. Patients received a conditioning chemotherapy regimen of cyclophosphamide and fludarabine followed by a single infusion of anti-CD19 CAR T cells.
Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response. CRs were obtained by four of seven evaluable patients with chemotherapy-refractory DLBCL; three of these four CRs are ongoing, with durations ranging from 9 to 22 months. Acute toxicities including fever, hypotension, delirium, and other neurologic toxicities occurred in some patients after infusion of anti-CD19 CAR T cells; these toxicities resolved within 3 weeks after cell infusion. One patient died suddenly as a result of an unknown cause 16 days after cell infusion. CAR T cells were detected in the blood of patients at peak levels, ranging from nine to 777 CAR-positive T cells/μL.
This is the first report to our knowledge of successful treatment of DLBCL with anti-CD19 CAR T cells. These results demonstrate the feasibility and effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells. The numerous remissions obtained provide strong support for further development of this approach.
Full-text · Article · Aug 2014 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: A large definitive trial comparing the use of sentinel lymph node biopsy and elective lymph node dissection to observation in patients with intermediate thickness melanomas fails to show improved melanoma-specific survival. These results demand reconsideration of the routine use of sentinel lymph node biopsy in the treatment of primary melanoma.
[Show abstract][Hide abstract] ABSTRACT: PURPOSEAdoptive cell therapy (ACT) with autologous tumor-infiltrating lymphocytes (TILs) and high-dose interleukin-2 (IL-2) administered to lymphodepleted patients with melanoma can cause durable tumor regressions. The optimal TIL product for ACT is unknown. PATIENTS AND METHODS
Patients with metastatic melanoma were prospectively assigned to receive unselected young TILs versus CD8(+)-enriched TILs. All patients received lymphodepleting chemotherapy and high-dose IL-2 therapy and were assessed for response, toxicity, survival, and immunologic end points.ResultsThirty-four patients received unselected young TILs with a median of 8.0% CD4(+) lymphocytes, and 35 patients received CD8(+)-enriched TILs with a median of 0.3% CD4(+) lymphocytes. One month after TIL infusion, patients who received CD8(+)-enriched TILs had significantly fewer CD4(+) peripheral blood lymphocytes (P = .01). Twelve patients responded to therapy with unselected young TILs (according to Response Evaluation Criteria in Solid Tumors [RECIST]), and seven patients responded to CD8(+)-enriched TILs (35% v 20%; not significant). Retrospective studies showed a significant association between response to treatment and interferon gamma secretion by the infused TILs in response to autologous tumor (P = .04), and in the subgroup of patients who received TILs from subcutaneous tumors, eight of 15 patients receiving unselected young TILs responded but none of eight patients receiving CD8(+)-enriched TILs responded. CONCLUSIONA randomized selection design trial was feasible for improving individualized TIL therapy. Since the evidence indicates that CD8(+)-enriched TILs are not more potent therapeutically and they are more laborious to prepare, future studies should focus on unselected young TILs.
Full-text · Article · May 2013 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: : Chronic granulomatous disease is a rare immunodeficiency complicated by dysregulated inflammation and granulomatous complications of the GI tract. The management of chronic granulomatous disease colitis presents the dilemma of an immunocompromised host requiring immunosuppressive therapy which can potentiate fatal infections.
: The aim of this study was to identify the types of GI surgery performed in patients and determine the role of surgery in the management of refractory colitis.
: A retrospective single-institution chart review was performed.
: Of 268 patients with chronic granulomatous disease treated at the National Institutes of Health between 1985 and 2011, 98 (37%) were identified as having colitis; 27 (10%) had a history of GI luminal surgery.
: Patient characteristics, type of GI surgery, and clinical outcomes were documented.
: A total of 62 GI luminal surgeries were performed in 27 patients with chronic granulomatous disease and colitis. All 27 had a history of perineal disease requiring intervention. Four (15%) had additional surgery performed for reasons other than colitis. Otherwise, 12 (44%) had surgery limited to the perineum, 2 (7%) had a segmental resection, and 13 (48%) underwent fecal diversion with ileostomy or colostomy. Despite local procedures, 7 (58%) patients in the perineal-only group remained symptomatic. Both patients with a segmental resection had persistent perineal disease, and 1 had a recurrent colovesicular fistula. Of the 13 ostomy patients, 11 initially received a diverting ostomy. Eight (73%) of these ultimately required additional procedures for refractory disease, and 4 (36%) developed peristomal pyoderma gangrenosum. Four patients who underwent proctocolectomy with end ileostomy, either initially (2) or as a definitive procedure (2), experienced resolution of colitis and perineal disease.
: This study is limited by its retrospective design, small sample size, and highly selected patient population.
: Proctocolectomy with end ileostomy may offer a definitive treatment in a patient with refractory chronic granulomatous disease colitis given current therapeutic limitations.
No preview · Article · May 2013 · Diseases of the Colon & Rectum
[Show abstract][Hide abstract] ABSTRACT: Seven patients with venous thrombosis and contraindications to traditional thrombolytic therapy, consisting of recent intracranial surgery, recent pineal or retroperitoneal hemorrhage, active genitourinary or gastrointestinal bleeding, epidural procedures, and impending surgery, were successfully treated with a modified thrombolytic regimen. To improve safety, prolonged continuous infusions of tissue plasminogen activator (tPA) was eliminated in favor of once-daily low-dose intraclot injections of tPA to minimize the amount and duration of tPA in the systemic circulation, and low-therapeutic or regional anticoagulation was used to reduce anticoagulant risks. These modifications may allow thrombolytic treatment for selected patients with severe venous thrombosis who are deemed to be at high risk.
No preview · Article · Jan 2013 · Journal of vascular and interventional radiology: JVIR
[Show abstract][Hide abstract] ABSTRACT: Nine cancer patients were treated with adoptive cell therapy using autologous anti-MAGE-A3 T-cell receptors (TCR)-engineered T cells. Five patients experienced clinical regression of their cancers including 2 on-going responders. Beginning 1-2 days postinfusion, 3 patients (#'s 5, 7, and 8) experienced mental status changes, and 2 patients (5 and 8) lapsed into comas and subsequently died. Magnetic resonance imagining analysis of patients 5 and 8 demonstrated periventricular leukomalacia, and examination of their brains at autopsy revealed necrotizing leukoencephalopathy with extensive white matter defects associated with infiltration of CD3/CD8 T cells. Patient 7, developed Parkinson-like symptoms, which resolved over 4 weeks and fully recovered. Immunohistochemical staining of patient and normal brain samples demonstrated rare positively staining neurons with an antibody that recognizes multiple MAGE-A family members. The TCR used in this study recognized epitopes in MAGE-A3/A9/A12. Molecular assays of human brain samples using real-time quantitative-polymerase chain reaction, Nanostring quantitation, and deep-sequencing indicated that MAGE-A12 was expressed in human brain (and possibly MAGE-A1, MAGE-A8, and MAGE-A9). This previously unrecognized expression of MAGE-A12 in human brain was possibly the initiating event of a TCR-mediated inflammatory response that resulted in neuronal cell destruction and raises caution for clinical applications targeting MAGE-A family members with highly active immunotherapies.
Full-text · Article · Jan 2013 · Journal of immunotherapy (Hagerstown, Md.: 1997)
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Autosomal dominant hyperimmunoglobulinemia E syndrome (HIES), also called Job's syndrome, is a primary immunodeficiency characterized by the triad of elevated immunoglobulin E levels, eczema, and infections. Its clinical course manifests as recurrent skin and pulmonary infections, and variable skeletal, connective tissue, and vascular abnormalities. There is evidence of abnormal tissue remodeling with pneumatocoeles frequently complicating pyogenic pneumonias and leading to secondary infections that cause the majority of morbidity and mortality. Complications are known to occur after lung surgery with a high frequency of bronchopleural fistulae, but little has been reported concerning abdominal surgeries.
Here, we report on the outcome and safety of two separate complex cases (hepatectomy and subtotal gastrectomy) and document our entire experience with abdominal surgical procedures performed on patients with HIES. Despite initial complications, all patients eventually made a full recovery.
As HIES patients now frequently live beyond the third and fourth decade, surgical issues similar to those in the general population may increase. Complex surgical procedures can be performed safely and benefit select patients with HIES, but benefit strongly from multidisciplinary teams and awareness of complications related to abnormal healing. We discuss current treatment and potential complications post-operatively in patients with HIES.
No preview · Article · Nov 2012 · Journal of Gastrointestinal Surgery
[Show abstract][Hide abstract] ABSTRACT: Treatment with ipilimumab can cause objective tumor responses in patients with metastatic melanoma. We have treated 177 evaluable patients in three clinical trials and have long-term follow-up to evaluate the durability of responses.
Patients with metastatic melanoma were treated in three trials from 2002 to 2005. In protocol 1, 56 patients received ipilimumab with gp100 peptides. In protocol 2, 36 patients received ipilimumab with interleukin-2. In protocol 3, 85 patients received ipilimumab with intrapatient dose-escalation and were randomized to receive gp100 peptides. We have analyzed their long-term follow-up and survival data.
With median follow-up for protocols 1, 2, and 3 being 92, 84, and 71 months, median survival was 14, 16, and 13 months with 5-year survival rates being 13%, 25%, and 23%, respectively. Patients in protocol 2 had a 17% complete response (CR) rate, compared with 7% in protocol 1 and 6% in protocol 3. These CR rates are higher than previously reported for the same trials because some patients who eventually became complete responders had continual tumor regression months to years after therapy. All but one of the 15 complete responders are ongoing at 54+ to 99+ months.
This report provides the longest follow-up of patients with melanoma treated with ipilimumab and shows that ipilimumab can induce durable, potentially curative tumor regression in a small percentage of patients with metastatic melanoma. The combination of ipilimumab and interleukin-2 seems to have an increased CR rate, but this needs to be tested in a randomized trial.
Full-text · Article · Jan 2012 · Clinical Cancer Research
[Show abstract][Hide abstract] ABSTRACT: We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFNγ and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFNγ and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFNγ ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions.
[Show abstract][Hide abstract] ABSTRACT: The aim of the study is to analyze treatment-induced gonadal damage and premature ovarian failure after adoptive cell therapy (ACT) after a cytotoxic lymphodepleting preparative regimen. Records of 66 consecutive females who received ACT at the Surgery Branch, National Cancer Institute, NIH (Bethesda, MD) were reviewed. Patients received a conditioning regimen of high-dose cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m² x 5 doses). Some patients also received total body radiation at 200 or 600 cGy. Assessment of ovarian function was determined by analysis of monthly follicle stimulating hormone (FSH) levels, menstrual history, and symptoms. Among patients with serum available and normal pretreatment ovarian function, 21 had a preparative regimen with chemotherapy alone and 5 patients had received chemotherapy with total body radiation. Nine (43%) patients in the chemotherapy cohort and all 5 patients in the chemotherapy plus total body radiation cohort had persistently elevated FSH levels and were given the diagnosis of premature ovarian failure. Twelve (57%) patients had normal FSH levels at 6 months posttreatment. Median age of all patients at treatment was 34 years. Median age of women retaining normal ovarian function was 30 (range, 19-45) vs. 41 years (range, 30-49) for those who did not regain function. The conditioning regimen of 2 doses of cyclophosphamide (60 mg/kg) and 5 doses of fludarabine (25 mg/m²) may induce gonadal damage and premature ovarian failure. Younger age at treatment was associated with a higher frequency of normal ovarian function posttreatment, whereas adding total body radiation was associated with a high risk of ovarian failure.
Full-text · Article · May 2011 · Journal of immunotherapy (Hagerstown, Md.: 1997)