Characteristics of Malignant Pleural Effusion Resident CD8+ T Cells from a Heterogeneous Collection of Tumors.

While T cell-based cancer immunotherapies have shown great promise, there remains a need to understand how individual metastatic tumor environments impart local T cell dysfunction. At advanced stages, cancers that metastasize to the pleural space can result in a malignant pleural effusion (MPE) that harbors abundant tumor and immune cells, often exceeding 108 leukocytes per liter. Unlike other metastatic sites, MPEs are readily and repeatedly accessible via indwelling catheters, providing an opportunity to study the interface between tumor dynamics and immunity. In the current study, we examined CD8+ T cells within MPEs collected from patients with heterogeneous primary tumors and at various stages in treatment to determine (1) if these cells possess anti-tumor activity following removal from the MPE, (2) factors in the MPE that may contribute to their dysfunction, and (3) the phenotypic changes in T cell populations that occur following ex vivo expansion. Co-cultures of CD8+ T cells with autologous CD45- tumor containing cells demonstrated cytotoxicity (p = 0.030) and IFNγ production (p = 0.003) that inversely correlated with percent of myeloid derived suppressor cells, lactate, and lactate dehydrogenase (LDH) within the MPE. Ex vivo expansion of CD8+ T cells resulted in progressive differentiation marked by distinct populations expressing decreased CD45RA, CCR7, CD127, and increased inhibitory receptors. These findings suggest that MPEs may be a source of tumor-reactive T cells and that the cellular and acellular components suppress optimal function.

Metastasectomy for Tumor-Infiltrating Lymphocytes: An Emerging Operative Indication in Surgical Oncology.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TILs) is an emerging immunotherapy for metastatic cancer. Surgeons play a central role in ACT treatments by performing resection of tumors from which TILs are isolated. It is important that surgeons have familiarity with this emerging treatment method because it is increasingly performed for an expanding variety of solid tumors at institutions around the world. This report offers a brief introduction to ACT for cancer, highlights historical milestones in its development, and provides patient selection and operative considerations for surgeons called upon to perform metastasectomy for the purpose of isolating TILs.

Correction to: Metastasectomy for Tumor-Infiltrating Lymphocytes: An Emerging Operative Indication in Surgical Oncology.

In the original article the middle initial of Nicholas D. Klemen was inadvertently omitted. On the first page of the original article, under the heading A Novel Way to Fight Cancer, there was an error in the third sentence. The corrected text is as follows: For example, the presence of T cells within tumors of colorectal origin can be a superior predictor of patient survival compared with the standard histopathologic methods currently used to stage colorectal cancer.6,7.

Treatment of metastatic uveal melanoma with adoptive transfer of tumour-infiltrating lymphocytes: a single-centre, two-stage, single-arm, phase 2 study.

BACKGROUND: Uveal melanoma is a rare tumour with no established treatments once metastases develop. Although a variety of immune-based therapies have shown efficacy in metastatic cutaneous melanoma, their use in ocular variants has been disappointing. Recently, adoptive T-cell therapy has shown salvage responses in multiple refractory solid tumours. Thus, we sought to determine if adoptive transfer of autologous tumour-infiltrating lymphocytes (TILs) could mediate regression of metastatic uveal melanoma. METHODS: In this ongoing single-centre, two-stage, phase 2, single-arm trial, patients (aged ≥16 years) with histologically confirmed metastatic ocular melanoma were enrolled. Key eligibility criteria were an Eastern Cooperative Oncology Group performance status of 0 or 1, progressive metastatic disease, and adequate haematological, renal, and hepatic function. Metastasectomies were done to procure tumour tissue to generate autologous TIL cultures, which then underwent large scale ex-vivo expansion. Patients were treated with lymphodepleting conditioning chemotherapy (intravenous cyclophosphamide [60 mg/kg] daily for 2 days followed by fludarabine [25 mg/m2] daily for 5 days, followed by a single intravenous infusion of autologous TILs and high-dose interleukin-2 [720 000 IU/kg] every 8 h). The primary endpoint was objective tumour response in evaluable patients per protocol using Response to Evaluation Criteria in Solid Tumors, version 1.0. An interim analysis of this trial is reported here. The trial is registered at ClinicalTrials.gov, number NCT01814046. FINDINGS: From the completed first stage and ongoing expansion stage of this trial, a total of 21 consecutive patients with metastatic uveal melanoma were enrolled between June 7, 2013, and Sept 9, 2016, and received TIL therapy. Seven (35%, 95% CI 16-59) of 20 evaluable patients had objective tumour regression. Among the responders, six patients achieved a partial response, two of which are ongoing and have not reached maximum response. One patient achieved complete response of numerous hepatic metastases, currently ongoing at 21 months post therapy. Three of the responders were refractory to previous immune checkpoint blockade. Common grade 3 or worse toxic effects were related to the lymphodepleting chemotherapy regimen and included lymphopenia, neutropenia, and thrombocytopenia (21 [100%] patients for each toxicity); anaemia (14 [67%] patients); and infection (six [29%] patients). There was one treatment-related death secondary to sepsis-induced multiorgan failure. INTERPRETATION: To our knowledge, this is the first report describing adoptive transfer of autologous TILs to mediate objective tumour regression in patients with metastatic uveal melanoma. These initial results challenge the belief that metastatic uveal melanoma is immunotherapy resistant and support the further investigation of immune-based therapies for this cancer. Refinement of this T-cell therapy is crucial to improve the frequency of clinical responses and the general applicability of this treatment modality. FUNDING: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

Metastasectomy Following Immunotherapy with Adoptive Cell Transfer for Patients with Advanced Melanoma.

BACKGROUND: Immunotherapeutic treatment strategies including adoptive cell transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated. METHODS: Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes. RESULTS: Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS. CONCLUSIONS: Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase the role of surgery for patients with advanced disease.

B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells.

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.

Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment.

Hepatocellular carcinoma (HCC) is an aggressive malignancy mainly due to metastases or postsurgical recurrence. We postulate that metastases are influenced by the liver microenvironment. Here, we show that a unique inflammation/immune response-related signature is associated with noncancerous hepatic tissues from metastatic HCC patients. This signature is principally different from that of the tumor. A global Th1/Th2-like cytokine shift in the venous metastasis-associated liver microenvironment coincides with elevated expression of macrophage colony-stimulating factor (CSF1). Moreover, a refined 17 gene signature was validated as a superior predictor of HCC venous metastases in an independent cohort, when compared to other clinical prognostic parameters. We suggest that a predominant humoral cytokine profile occurs in the metastatic liver milieu and that a shift toward anti-inflammatory/immune-suppressive responses may promote HCC metastases.

Uveal melanoma immunogenomics predict immunotherapy resistance and susceptibility.

Immune checkpoint inhibition has shown success in treating metastatic cutaneous melanoma but has limited efficacy against metastatic uveal melanoma, a rare variant arising from the immune privileged eye. To better understand this resistance, we comprehensively profile 100 human uveal melanoma metastases using clinicogenomics, transcriptomics, and tumor infiltrating lymphocyte potency assessment. We find that over half of these metastases harbor tumor infiltrating lymphocytes with potent autologous tumor specificity, despite low mutational burden and resistance to prior immunotherapies. However, we observe strikingly low intratumoral T cell receptor clonality within the tumor microenvironment even after prior immunotherapies. To harness these quiescent tumor infiltrating lymphocytes, we develop a transcriptomic biomarker to enable in vivo identification and ex vivo liberation to counter their growth suppression. Finally, we demonstrate that adoptive transfer of these transcriptomically selected tumor infiltrating lymphocytes can promote tumor immunity in patients with metastatic uveal melanoma when other immunotherapies are incapable.

A novel nomogram for peritoneal mesothelioma predicts survival.

BACKGROUND: Malignant peritoneal mesothelioma (MPM) is a rare disease treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Estimation of personalized survival times can potentially guide treatment and surveillance. METHODS: We analyzed 104 patients who underwent CRS and cisplatin-based HIPEC for MPM. By means of 25 demographic, laboratory, operative, and histopathological variables, we developed a novel nomogram using machine-learned Bayesian belief networks with stepwise training, testing, and cross-validation. RESULTS: The mean peritoneal carcinomatosis index (PCI) was 15, and 66 % of patients had a completeness of cytoreduction (CC) score of 0 or 1. Eighty-seven percent of patients had epithelioid histology. The median follow-up time was 49 (1-195) months. The 3- and 5-year overall survivals (OS) were 58 and 46 %, respectively. The histological subtype, pre-CRS PCI, and preoperative serum CA-125 had the greatest impact on OS and were included in the nomogram. The mean areas under the receiver operating characteristic curve for the 10-fold cross-validation of the 3- and 5-year models were 0.77 and 0.74, respectively. The graphical calculator or nomogram uses color coding to assist the clinician in quickly estimating individualized patient-specific survival before surgery. CONCLUSIONS: Machine-learned Bayesian belief network analysis generated a novel nomogram predicting 3- and 5-year OS in patients treated with CRS and HIPEC for MPM. Pre-CRS estimation of survival times may potentially individualize patient care by influencing the use of systemic therapy and frequency of diagnostic imaging, and might prevent CRS in patients unlikely to achieve favorable outcomes despite surgical intervention.

T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis.

Autologous T lymphocytes genetically engineered to express a murine T cell receptor (TCR) against human carcinoembryonic antigen (CEA) were administered to three patients with metastatic colorectal cancer refractory to standard treatments. All patients experienced profound decreases in serum CEA levels (74-99%), and one patient had an objective regression of cancer metastatic to the lung and liver. However, a severe transient inflammatory colitis that represented a dose limiting toxicity was induced in all three patients. This report represents the first example of objective regression of metastatic colorectal cancer mediated by adoptive T cell transfer and illustrates the successful use of a TCR, raised in human leukocyte antigen (HLA) transgenic mice, against a human tumor associated antigen. It also emphasizes the destructive power of small numbers of highly avid T cells and the limitations of using CEA as a target for cancer immunotherapy.

Minimally invasive liver resection to obtain tumor-infiltrating lymphocytes for adoptive cell therapy in patients with metastatic melanoma.

BACKGROUND: Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TIL) in patients with metastatic melanoma has been reported to have a 56% overall response rate with 20% complete responders. To increase the availability of this promising therapy in patients with advanced melanoma, a minimally invasive approach to procure tumor for TIL generation is warranted. METHODS: A feasibility study was performed to determine the safety and efficacy of laparoscopic liver resection to generate TIL for ACT. Retrospective review of a prospectively maintained database identified 22 patients with advanced melanoma and visceral metastasis (AJCC Stage M1c) who underwent laparoscopic liver resection between 1 October 2005 and 31 July 2011. The indication for resection in all patients was to receive postoperative ACT with TIL. RESULTS: Twenty patients (91%) underwent resection utilizing a closed laparoscopic technique, one required hand-assistance and another required conversion to open resection. Median intraoperative blood loss was 100 mL with most cases performed without a Pringle maneuver. Median hospital stay was 3 days. Three (14%) patients experienced a complication from resection with no mortality. TIL were generated from 18 of 22 (82%) patients. Twelve of 15 (80%) TIL tested were found to have in vitro tumor reactivity. Eleven patients (50%) received the intended ACT. Two patients were rendered no evidence of disease after surgical resection, with one undergoing delayed ACT with generated TIL after relapse. Objective tumor response was seen in 5 of 11 patients (45%) who received TIL, with one patient experiencing an ongoing complete response (32+ months). CONCLUSIONS: Laparoscopic liver resection can be performed with minimal morbidity and serve as an effective means to procure tumor to generate therapeutic TIL for ACT to patients with metastatic melanoma.

Genome-wide gain-of-function screening characterized lncRNA regulators for tumor immune response.

The majority of lncRNAs' roles in tumor immunology remain elusive. This project performed a CRISPR activation screening of 9744 lncRNAs in melanoma cells cocultured with human CD8+ T cells. We identified 16 lncRNAs potentially regulating tumor immune response. Further integrative analysis using tumor immunogenomics data revealed that IL10RB-DT and LINC01198 are significantly correlated with tumor immune response and survival in melanoma and breast cancer. Specifically, IL10RB-DT suppresses CD8+ T cells activation via inhibiting IFN-γ-JAK-STAT1 signaling and antigen presentation in melanoma and breast cancer cells. On the other hand, LINC01198's up-regulation sensitizes the killing of tumor cells by CD8+ T cells. Mechanistically, LINC01198 interacts and activates NF-κB component p65 to trigger the type I and type II interferon responses in melanoma and breast cancer cells. Our study systematically characterized novel lncRNAs involved in tumor immune response.

Liver resection and ablation for metastatic adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease without effective chemotherapy treated most appropriately with resection. The aim of this study was to evaluate our experience with liver resection for metastatic ACC. METHODS: This study is a retrospective review of patients who underwent liver resection or radiofrequency ablation (RFA) for ACC from 1979 to 2009. RESULTS: A total of 27 patients were identified. Of the 27, 19 underwent liver resection. Of the 19, 10 had a single liver lesion, and 18 of 19 were rendered free of disease in the liver, although only 11 of 19 were rendered completely free of disease because of extrahepatic disease (EHD). Of the 19, 13 had synchronous EHD. Also, 6 of 17 remained disease free in the liver at a median follow-up of 6.2 years (status of 2 of 19 was unknown). Of the 27 patients, 8 underwent RFA, 7 of 8 became free of disease in the liver, and 5 of 7 had EHD. No patients responded to prior chemotherapy. Median overall survival and survival of patients who underwent liver resection or RFA were both 1.9 years (0.2-12 + years); 5-year actuarial survivals were 29% and 29%, respectively. Disease-free interval (DFI) greater than 9 months from primary resection was associated with longer survival (median 4.1 vs 0.9 years; P = .013). CONCLUSIONS: This study is a tertiary institution series of liver resection and RFA for ACC. Given the lack of effective systemic treatment options and the safety of resection and ablation, liver resection or RFA may be considered in selected patients with ACC metastatic to the liver especially with a long DFI.

Gene therapy with human and mouse T-cell receptors mediates cancer regression and targets normal tissues expressing cognate antigen.

Gene therapy of human cancer using genetically engineered lymphocytes is dependent on the identification of highly reactive T-cell receptors (TCRs) with antitumor activity. We immunized transgenic mice and also conducted high-throughput screening of human lymphocytes to generate TCRs highly reactive to melanoma/melanocyte antigens. Genes encoding these TCRs were engineered into retroviral vectors and used to transduce autologous peripheral lymphocytes administered to 36 patients with metastatic melanoma. Transduced patient lymphocytes were CD45RA(-) and CD45RO(+) after ex vivo expansion. After infusion, the persisting cells displayed a CD45RA(+) and CD45RO(-) phenotype. Gene-engineered cells persisted at high levels in the blood of all patients 1 month after treatment, responding patients with higher ex vivo antitumor reactivity than nonresponders. Objective cancer regressions were seen in 30% and 19% of patients who received the human or mouse TCR, respectively. However, patients exhibited destruction of normal melanocytes in the skin, eye, and ear, and sometimes required local steroid administration to treat uveitis and hearing loss. Thus, T cells expressing highly reactive TCRs mediate cancer regression in humans and target rare cognate-antigen-containing cells throughout the body, a finding with important implications for the gene therapy of cancer. This trial was registered at www.ClinicalTrials.gov as NCI-07-C-0174 and NCI-07-C-0175.

In Vivo Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy.

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8+ T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8+ T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8+ T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rα in vivo priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.

LincRNA-immunity landscape analysis identifies EPIC1 as a regulator of tumor immune evasion and immunotherapy resistance.

Through an integrative analysis of the lincRNA expression and tumor immune response in 9,626 tumor samples across 32 cancer types, we developed a lincRNA-based immune response (LIMER) score that can predict the immune cells infiltration and patient prognosis in multiple cancer types. Our analysis also identified tumor-specific lincRNAs, including EPIC1, that potentially regulate tumor immune response in multiple cancer types. Immunocompetent mouse models and in vitro co-culture assays demonstrated that EPIC1 induces tumor immune evasion and resistance to immunotherapy by suppressing tumor cell antigen presentation. Mechanistically, lincRNA EPIC1 interacts with the histone methyltransferase EZH2, leading to the epigenetic silencing of IFNGR1, TAP1/2, ERAP1/2, and MHC-I genes. Genetic and pharmacological inhibition of EZH2 abolish EPIC1's immune-related oncogenic effect and its suppression of interferon-γ signaling. The EPIC1-EZH2 axis emerges as a potential mechanism for tumor immune evasion that can serve as therapeutic targets for immunotherapy.

Oncolytic virus promotes tumor-reactive infiltrating lymphocytes for adoptive cell therapy.

Adoptive cell therapy (ACT) using tumor-specific tumor-infiltrating lymphocytes (TILs) has demonstrated success in patients where tumor-antigen specific TILs can be harvested from the tumor, expanded, and re-infused in combination with a preparatory regimen and IL2. One major issue for non-immunogenic tumors has been that the isolated TILs lack tumor specificity and thus possess limited in vivo therapeutic function. An oncolytic virus (OV) mediates an immunogenic cell death for cancer cells, leading to elicitation and dramatic enhancement of tumor-specific TILs. We hypothesized that the tumor-specific TILs elicited and promoted by an OV would be a great source for ACT for solid cancer. In this study, we show that a local injection of oncolytic poxvirus in MC38 tumor with low immunogenicity in C57BL/6 mice, led to elicitation and accumulation of tumor-specific TILs in the tumor tissue. Our analyses indicated that IL2-armed OV-elicited TILs contain lower quantities of exhausted PD-1hiTim-3+ CD8+ T cells and regulatory T cells. The isolated TILs from IL2-expressing OV-treated tumor tissue retained high tumor specificity after expansion ex vivo. These TILs resulted in significant tumor regression and improved survival after adoptive transfer in mice with established MC38 tumor. Our study showcases the feasibility of using an OV to induce tumor-reactive TILs that can be expanded for ACT.

Cytologic Evaluation of Tumor-Infiltrating Lymphocytes for Adoptive Cell Therapy.

OBJECTIVES: Novel immunotherapeutic options for refractory metastatic cancer patients include adoptive cell therapies such as tumor infiltrating lymphocytes (TILs). This study characterizes the clinicopathologic findings in a cohort of TIL specimens. METHODS: Patients with metastatic malignancy who were eligible had TILs from their metastases grown and expanded and then sent to pathology. RESULTS: A total of 11 TIL specimens (10 melanoma, 1 adenocarcinoma) from patients enrolled in an experimental clinical trial were reviewed. All specimens showed more than 200 lymphoid cells, stained positive for lymphoid markers confirming an activated cytotoxic T-cell immunophenotype, and morphologically showed an intermediate-sized population with immature chromatin and frequent mitoses. Six cases (55%) showed large cells with nucleomegaly and prominent nucleoli. CONCLUSIONS: This report is the first describing cytopathologic findings of autologous TIL therapy including adequacy guidelines and expected cytomorphologic and immunophenotypic findings. To meet this novel clinical demand, a predefined cytology protocol to rapidly process and interpret these specimens needs to be established.

Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines.

PURPOSE: To identify prognostic factors associated with survival beyond 4 years and overall response in patients with metastatic melanoma treated with high-dose bolus i.v. interleukin-2 (IL-2) given either alone or in combination with a variety of melanoma vaccines. STUDY DESIGN: 684 consecutive patients with metastatic melanoma received high-dose bolus i.v. IL-2 either alone or in conjunction with a variety of melanoma vaccines. Treatments occurred between August 1, 1985 and January 1, 2006. RESULTS: The overall objective response rate was 13% for patients receiving IL-2 alone and 16% for patients who received IL-2 with vaccine. In patients treated with IL-2 alone (n=305) and IL-2 with vaccine (n=379), having an objective response was associated with survival beyond 4 years (P<0.0001). No pretreatment factors could be identified that were strongly associated with increased rate of objective response or long-term survival in patients receiving IL-2 alone. In patients receiving IL-2 with vaccines, there were increased response rates in patients with s.c. or cutaneous disease only and lower response rates with visceral disease only. Patients who received the gp100:209-217(210M) peptide plus IL-2 showed a strong trend to increased objective responses compared with IL-2 alone (22% versus 12.8%; P=0.01) and also compared with patients who received a variety of vaccines that did not include this immunogenic peptide (13.8%; P=0.009). CONCLUSION: IL-2 can produce a modest response rate in patients with metastatic melanoma including patients with durable complete responses. S.c. or cutaneous disease only and vaccination with gp100:209-217(210M) peptide was associated with significant increase in response rates.

A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus-associated Epithelial Cancers.

PURPOSE: Cellular therapy is an emerging cancer treatment modality, but its application to epithelial cancers has been limited. This clinical trial evaluated tumor-infiltrating lymphocyte (TIL) therapy for the treatment of patients with metastatic human papillomavirus (HPV)-associated carcinomas. PATIENTS AND METHODS: The trial was a phase II design with two cohorts, cervical cancers and noncervical cancers. Cell infusion was preceded by a lymphocyte-depleting conditioning regimen and followed by systemic high-dose aldesleukin. RESULTS: Objective tumor responses occurred in 5 of 18 (28%) patients in the cervical cancer cohort and 2 of 11 (18%) patients in the noncervical cancer cohort. Two of the responses in cervical cancer were complete and are ongoing 67 and 53 months after treatment. Responses in the noncervical cancer cohort were in anal cancer and oropharyngeal cancer. The HPV reactivity of the infused T cells correlated with clinical response. Peripheral blood repopulation with HPV-reactive T cells also correlated with clinical response. CONCLUSIONS: These findings support the concept that cellular therapy can mediate the regression of epithelial cancers, and they suggest the importance of predictive biomarkers and novel treatment platforms for more effective therapies.