Long-term Complete Response Research Articles

Long-term Follow-up and Correlative Analysis of Two Phase II Trials of Rituximab and Lenalidomide Followed by Continuous Lenalidomide in Untreated and Relapsed/Refractory Indolent Lymphoma.

Rituximab and lenalidomide are effective for previously untreated and relapsed/refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). However, long-term survival and predictive biomarkers are not well described. We conducted two phase II open-label trials involving 60 patients with previously untreated and R/R advanced-stage iNHL. Patients received lenalidomide and rituximab induction followed by continuous lenalidomide until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Correlative studies included plasma cytokine monitoring, flow cytometry of peripheral blood mononuclear cells (PBMC; days 0, 15, 30, and 60), and RNA sequencing (RNA-seq) of pretreatment tumor biopsies. At a median follow-up of 63 months for previously untreated and 100 months for R/R, ORR was 82% for both. The 11 R/R patients who achieved complete remission remained in continuous remission for 16 to 141 months, thereafter. Median overall survival (OS) was not reached in the previously untreated and was 140 months (95% confidence interval, 53.4-140) in the R/R group. A mixed-effects linear regression model identified significant associations between Granzyme B+ (GranB+) CD8+ T cells and long-term complete response (LTCR; P = 5.3e-4). Furthermore, prior to start of therapy, treatment response could be predicted by B-cell and GranB+ CD8+ T-cell levels (% total lymphocytes). Rituximab plus lenalidomide followed by continuous lenalidomide is effective with manageable toxicity in patients with previously untreated and R/R iNHL. This regimen produces durable remissions, even in heavily pretreated patients, with some lasting greater than 10 years. GranB+ CD8+ T cells, B cells, and plasma IFNγ allowed prediction of LTCR but need validation in larger trials.

Anti-PD-L1 treatment to enhance the response of glioblastoma to radiation and produce long-term survival in mice.

e14048 Background: Glioblastoma (GBM) is the most aggressive and most common primary central nervous system cancer in adults. Blocking the interaction between Programmed Cell Death Protein-1 (PD-1) and its ligand (PD-L1) has shown remarkable success in the treatment of several cancers. However, many challenges remain in improving the efficacy of using monoclonal antibodies (Ab) against the receptor PD-1 in GBM, mainly due to the “non-immunogenic” tumor characteristics of GBM. PD-L1 has been found to be overexpressed on the surface of human GBM tumor cells and tumor-associated macrophages (TAM). Radiotherapy (RT), as one of the standard therapy of GBM, could alter the tumor microenvironment and promote an antitumor immune response. We hypothesize that anti-PD-L1 therapy can enhance the RT effects and improve the outcome of treatment when combined. Methods: Using a preclinical orthotropic syngeneic CT-2A mouse GBM tumor model, we studied the efficacy of combined therapy with anti-PD-L1 and RT. Mice were stratified into four treatment groups: control, RT, anti-PD-L1 Ab, and anti-PD-L1 Ab plus RT. RT(8 Gy) was given one time simultaneously with the first dose of anti-PD-L1, followed by systemic anti-PD-L1 maintenance treatment to the mice. Overall survival and tumor growth were monitored. Immunohistochemistry on resected tumors during treatment was performed to characterize the immune response. Single-cell RNA sequencing (scRNA-seq) was also performed to further study the immunologic parameters in the mouse brain. Results: Our results showed that anti-PD-L1 Ab in combination with RT provided a remarkable antitumor immune response and improved overall survival, with 25.5, 34, and 30 days of median survival in control (no-treatment), RT, and anti-PD-L1 groups, respectively, and achieving long-term survival and complete tumor response in 80% of the mice in the anti-PD-L1+RT treatment group (median survival not reached) in GBM tumor-bearing mice. The combined therapy promoted the recruitment of tumor-infiltrating immune cells, reversed the hostile tumor immune environment with a higher M1/TAM ratio, CD8+ /CD4+ T cell ratio, and CD8+ T cell /Treg cell ratio in the tumor area comparing with those parameters in single modality treatment groups. Furthermore, scRNA-seq data demonstrated that anti-PD-L1 combined with RT resulted in robust higher CD8 effector T cells, while lower CD4 and CD8 exhausted T cells in the tumor region compared to other groups. Increased CD4 central memory T cells and CD8 central memory T cells were seen only in tumors treated with anti-PD-L1+RT providing immunologic explanations on the durable control of GBM achieved only by the combined therapy. Conclusions: The anti-PD-L1 therapy synergizes with RT by reversing the hostile tumor immune environment resulting in improved tumor control and long-term survival in the syngeneic mouse GBM model.

Boosting Immunity against Multiple Myeloma.

Simple SummaryMultiple myeloma is a hematological malignancy arising from the proliferation of tumor antibody-producing cells in the bone marrow. In this cancer, tumor growth is facilitated by a permissive bone marrow microenvironment including dysfunctional immune cells that lose their ability to control cancer cells and become “toxic friends”. Immunotherapy is a form of cancer treatment that aims to stimulate the immune system to “fight back” tumor cells. Several immunotherapies have been approved for clinical use and many others are currently under clinical trials. In this review, we focus on current and future immunotherapies used in multiple myeloma with impact on bone marrow immune microenvironment cells, also known as the bone marrow immunome.Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

Abstract PS10-44: Termination of trastuzumab-based treatment after complete response in HER2-positive metastatic breast cancer

Abstract Background: Trastuzumab has been used for HER2 positive breast cancer treatment for more than 20 years. The ratio of HER2 overexpression in breast cancer patients is about 20%. In this study, we aim to evaluate the prognosis of HER2 positive breast cancer patients with long term received trastuzumab and examined the predictors of complete response. Method: In this study, we included the patients with HER2 positive metastatic breast cancer received long-term trastuzumab. Demographic, clinical, pathological, and treatment data of the patients retrospectively recorded. Response rates of trastuzumab-based treatment evaluated by RECIST. The prognosis of the patients and predictors of complete response assessed with Kaplan-Meier analysis and logistic regression analysis, respectively. Also, the prognosis of the patients whose trastuzumab-based treatment was terminated was evaluated. Results: Median follow-up was 123.3 months (range, 32.2-330.3). Eighty patients included the study, and the median age of the patients was 43 (22-68). The patients received trastuzumab-based treatment with a median of 62 months (range, 12-191). The number of de-novo metastatic patients was 27 (33.8%). All patients had a pathological HER2 overexpressed tumor that scored 3+ (71.3%) by ımmunohistochemistry (IHC) or scored 2+ (28.7%) by IHC confirmed with FISH. In all patients, five-, ten-, and, fifteen – years overall survival were 96.1%, 86.8%, and 60.5%, respectively. A complete response was detected at 60 (75%) of the patients. The median time to complete response was 14.4 months (range, 2.4-47.8). In logistic-regression analysis: age at diagnosis (p=0.543), menopausal status (p=0.074), bisphosphonates treatment (p=0.682), palliative radiotherapy (p=0.935), and de-novo metastatic disease (p=0.405) were not statistically significant predictors for complete response. However, the number of metastatic sites (p=0.016), and the use of endocrine therapy (p=0.019) with trastuzumab were statistically significant. During the study period, trastuzumab-based treatment of twelve patients was terminated, four (33.3%) patients continue to receive aromatase inhibitör, and eight (66.7%) patients received no treatment. After termination of trastuzumab, at a median follow-up 44.7 months (range, 11.6-66.6), recurrence was not detected in the patients. Conclusions: In this study, we found that trastuzumab-based therapy can provide full recovery of HER2 positive metastatic breast cancer. For the patients with a long-term complete response, discontinuation of trastuzumab-based treatment should be considered. Also, hormone-positive patients should continue to receive aromatase inhibitör. The use of endocrine therapy with trastuzumab and the number of metastatic sites are predictors of the complete response Citation Format: Izzet Dogan, Esra Aydın, Nijat Khanmammadov, Adnan Aydıner, Pınar Saip. Termination of trastuzumab-based treatment after complete response in HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-44.

A Case of Postoperative Intrapelvic Locally Recurrent Rectal Cancer in which Long-term Complete Response was Achieved after Chemoradiotherapy

A Case of Postoperative Intrapelvic Locally Recurrent Rectal Cancer in which Long-term Complete Response was Achieved after Chemoradiotherapy

Efficacy and Safety of Nivolumab Plus Ipilimumab versus Sunitinib in First-line Treatment of Patients with Advanced Sarcomatoid Renal Cell Carcinoma.

Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3-22.9); n = 65; HR, 0.45 (95% CI, 0.3-0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33-0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5.

Anti-BCMA Immunotoxins: Design, Production, and Preclinical Evaluation.

Multiple myeloma (MM) is a B-cell malignancy that is incurable for a majority of patients. B-cell maturation antigen (BCMA) is a lineage-restricted differentiation protein highly expressed in multiple myeloma cells but not in other normal tissues except normal plasma B cells. Due to the restricted expression and being a cell surface membrane protein, BCMA is an ideal target for immunotherapy approaches in MM. Recombinant immunotoxins (RITs) are a novel class of protein therapeutics that are composed of the Fv or Fab portion of an antibody fused to a cytotoxic agent. RITs were produced by expressing plasmids encoding the components of the anti-BCMA RITs in E. coli followed by inclusion body preparation, solubilization, renaturation, and purification by column chromatography. The cytotoxic activity of RITs was tested in vitro by WST-8 assays using BCMA expressing cell lines and on cells isolated from MM patients. The in vivo efficacy of RITs was tested in a xenograft mouse model using BCMA expressing multiple myeloma cell lines. Anti-BCMA recombinant immunotoxins are very effective in killing myeloma cell lines and cells isolated from myeloma patients expressing BCMA. Two mouse models of myeloma showed that the anti-BCMA immunotoxins can produce a long-term complete response and warrant further preclinical development.

Long-term sustained complete response with off-therapy to sorafenib in advanced hepatocellular carcinoma: a case report

Long-term sustained complete response with off-therapy to sorafenib in advanced hepatocellular carcinoma: a case report

A case of long-term complete response obtained by combination therapy with anticancer drugs and a dendric cell vaccine for gastric cancer with multiple liver metastasis

A case of long-term complete response obtained by combination therapy with anticancer drugs and a dendric cell vaccine for gastric cancer with multiple liver metastasis

Long Term Follow-up of a Phase II Study of Cladribine with Concurrent Rituximab in Patients with Hairy Cell Leukemia Variant

Background Hairy cell leukemia (HCL) variant (HCLv) is considered a separate, more aggressive entity compared to classic HCL. HCLv responds poorly to single-agent purine analog with complete response (CR) rates below 10% and overall response rates under 50%. Rituximab combined with purine-analog can improve response rate and duration, but long-term data have not been reported for HCLv, particularly regarding minimal residual disease (MRD). We therefore update the results of a phase II trial with cladribine and concurrent rituximab in patients with HCLv, previously reported for 10 of the 20 patients enrolled. Methods Patients with HCLv with 0 to 1 prior courses of cladribine, and/or 0-1 prior courses of rituximab, received cladribine (0.15 mg/kg days 1-5), with 8 weekly doses of rituximab (375 mg/m2) beginning day 1. The primary endpoint was to determine CR rate and secondary endpoints included evaluating minimal residual disease (MRD) by blood and bone marrow aspirate flow cytometry, and bone marrow biopsy immunohistochemistry. Patients were able to receive a 2nd course of rituximab ≥ 6 months after the first, if and when MRD was detected in blood. Results Twenty patients were enrolled. Median age was 67 (range: 42-86) years. No patients had prior concurrent cladribine-rituximab. Eight were previously untreated, 1 had only splenectomy, 6 had prior cladribine, 1 had prior cladribine and splenectomy, 1 had prior rituximab, 1 had prior rituximab and splenectomy, 1 had cladribine, rituximab, and splenectomy, and 1 had combination rituximab-containing chemotherapy followed by cladribine. Out of 20 patients receiving concurrent cladribine-rituximab (CDAR), the CR rate was 95% (95% CI: 75-100%). This CR rate was superior to a historical control group of 3 of 39 HCLv patients who achieved CR to cladribine alone (p<0.0001). Sixteen (80%, 95% CI: 56-94%) of 20 patients became MRD-free at 6 months; median duration of MRD-free CR was 72.0 months, with 9 of 16 still MRD-free at 5-108 (median 29.1) months. With median potential follow up of 88 months (range: 7-123 months), 10 patients received delayed rituximab and 4 re-achieved MRD-free CR. Six patients required alternative treatment and 6 patients died, 5 with HCLv including 1 with HCLv limiting treatment for lung cancer, and 1 with Parkinson's disease but still MRD-free. Time from progression of HCLv to death was 5.9-30.0 (median 28.1) months. Achieving MRD-free CR by 6 months after CDAR (16 vs 4 patients) was important for median progression free survival [PFS, unreached vs 17.4 mo, hazard ratio (HR) 0.031, 95% CI 0.003-0.29, p<0.0001] and overall survival (OS, unreached vs 38.2 months, HR infinite since all 4 MRD+ deaths were prior to deaths of 2 patients who achieved MRD-free CR, p<0.0001). A significant relationship between prior purine analog therapy or unmutated IGHV4-34 (n=7) status and either PFS or OS has not yet been observed. Conclusion Concurrent cladribine with rituximab is highly effective in HCLv irrespective of prior purine-analog treatment or IGHV4-34 status and should replace purine analog monotherapy as treatment. Patients with long-term MRD-free CR are being followed to determine whether concurrent cladribine-rituximab as 1st-3rd line systemic therapy can permanently eradicate HCLv. Patients who progress have limited OS. This provides a rationale for the testing of higher intensity approaches up front and the identification of additional treatment options for HCLv. Disclosures Kreitman: Genentech: Research Funding. OffLabel Disclosure: Rituximab for hairy cell leukemia

PCN331 HUMANISTIC BURDEN OF NEWLY DIAGNOSED VERSUS RELAPSED/REFRACTORY ACUTE MYELOID LEUKEMIA

Acute Myeloid Leukemia (AML) is an aggressive leukemia associated with poor overall survival. Patients with AML experience significant disease symptoms and treatment-related consequences that diminish health-related quality of life (HRQoL) and psychosocial well-being. The objective of this targeted literature review was to assess humanistic burden evidence in patients with newly diagnosed and relapsed/refractory (R/R) AML. Medline, Embase, and the Cochrane Library databases were searched via the Ovid platform for all relevant humanistic burden studies between 2013 and 2018. The search strategy combined terms including AML and disease burden, quality of life (QOL), HRQoL, patient preference among others. 11 unique humanistic burden studies including randomized clinical trials (n=3), prospective studies (n=5) and patient surveys (n=3) from North America and Europe met eligibility criteria. Studies included adult patients with AML (mean age: 52 to 73.2 years). The European Organisation for the Research and Treatment of Cancer core 30-item questionnaire (EORTC QLQ-C30) was reported in ∼50% of all QoL studies (n=5/11). Fatigue and pain were among the most common and severe symptoms reported across all studies. Patients with secondary or R/R AML reported worse HRQoL than patients with denovo AML. Achievement of remission was associated with markedly improved HRQoL after one year with similar trends for younger versus older patients (<60 vs ≥60 years). Younger and older patients (<60 vs ≥60 years) one year from diagnosis reported no differences in global health or fatigue. Patients obtaining complete response perceived improvement in global health, physical and emotional functioning, and symptoms burden. AML is a life-threatening condition. The disease and treatment-related toxicities cause distressing symptoms that worsen overall health status, significantly impair daily functioning, role-fulfillment and emotional health. Treatments with the potential to induce long-term remission and complete responses are needed to improve outcomes for this deadly disease.

Aggressive prolactinomas: how to manage?

Aggressive prolactinomas are defined as radiologically invasive tumors which cannot be cured by surgery, and that have an unusually rapid rate of tumor growth despite dopamine agonist treatment and surgery. In some cases, metastasis occurs, defining prolactin carcinoma which is the second most frequent pituitary carcinoma. A literature search was performed to review the available data on the treatment of aggressive pituitary prolactinomas or carcinomas. When optimal standard therapies (high dose cabergoline, surgery and radiotherapy) failed, temozolomide, an alkylating drug, is currently the best option, allowing to control tumor growth in about 50% of treated prolactinomas and improving overall survival of these patients. However, long-term complete response occurs in a limited subgroup of tumors. Alternative drugs could be discussed in a subset of aggressive prolactinomas either before temozolomide (pasireotide, peptide receptor radionuclide therapy…) or after temozolomide failure. Despite the significant improvement obtained with the use of temozolomide, a need for alternative drugs persists since a majority of these tumors are resistant or will recur during the follow-up. Patients suffering from such a rare condition should have access to clinical trials available for other types of rare cancers, such as tyrosine kinase inhibitors or immunotherapy.

313P - Genome copy number alteration burden represents predictor of response in long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer

BackgroundThe introduction of anti-HER2 therapies such as trastuzumab for HER2+ metastatic breast cancer (MBC) has led to significant improvements to disease progression. We, and others have reported cases of long-term durable complete response to trastuzumab in HER2+ MBC. However, to-date only clinical and molecular analysis of this “exceptional” cohort exists. We hypothesise that genomic copy number alteration (CNA) burden can act as a prognostic measure of predicting response to trastuzumab in long-term never relapse exceptional responders (ExRs) from rapid non-responders (NR). MethodsWe performed whole exome sequencing (WES) on n=6 never relapse ExRs (med RFS < 149mo) and n=5 corresponding NRs (median RFS < 14mo). Both tumour and adjacent normal tissue (where available) was sequenced by BGI using the NGS illumina HiSeq PR100 (2 x 100bp) at a mean depth of 56 x. Reads were aligned to the hg19 reference genome using BWA software. Two-sample t-test with unequal variances was used to evaluate total genome CNA burden. Median CNA burden was used to stratify patients into high and low CNA burden groups, binary CNA stratification groups were further assessed using Kaplan-Meier survival estimation. ResultsWe analysed the DNA chromosome disruption (fraction of the genome amplified/deleted) and present CNA burden. We observed the overall fraction of genome CNA burden was more destructed (P=0.07); while more significantly pronounced in the amplification of the whole genome (P=0.03) in NR compared to ExRs. We further delineated the distribution of CNA burden in all genomes and identified chromosome 8 as significantly disrupted in NRs (P=0.02). Kaplan Meier survival analysis revealed that low total CNA burden at Chr8 and Chr17 conferred a statistically significant benefit in overall survival (P=0.009 and P=0.016, log rank). ConclusionsCNA burden in HER2+ MBC exceptional responders may represent a novel prognostic predictor to trastuzumab response. Our investigation of genome-wide CNA burden offers the potential to gain insight into the underlying genetic landscape of long-term, never relapse exceptional response to trastuzumab. Legal entity responsible for the studyThe authors. FundingCancer Clinical Research Trust. DisclosureG. Gullo: Honoraria (self): Genomic Health; Travel / Accommodation / Expenses: Roche. J. Crown: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Shareholder / Stockholder / Stock options: OncoMark; Honoraria (self): Amgen; Honoraria (self), Research grant / Funding (institution): Puma Technology; Honoraria (self), Advisory / Consultancy: Seattle Genetics; Honoraria (self), Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self): Vertex; Honoraria (self): Genomic Health; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self): MSD Oncology. All other authors have declared no conflicts of interest.

Longitudinal Evaluation of Minimal Residual Disease in Patients with Multiple Myeloma who Achieve Complete Response After First Line Therapy

Novel treatments have significantly increased the rates of complete response (CR) in patients with multiple myeloma (MM), however most of them will eventually relapse. The presence of minimal residual disease (MRD) has emerged as a valuable biomarker as it discriminates patients with a higher risk of progression despite the achievement of CR. Previous studies have highlighted the prognostic value of MRD negativity at the time of CR after frontline therapy; there is limited data on the impact of MRD in patients achieving long-term CR.

Evolving role of cytoreductive nephrectomy in metastatic renal cell carcinoma of variant histology.

Summarize current evidence for cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (mRCC) of variant histology. The mainstream treatment for advanced malignancy is systematic therapy, including chemotherapy, targeted therapy, and immunotherapy. Nonetheless, cytoreductive nephrectomy has been used in the management of mRCC including variant (nonclear cell) histology. Prospective data supported cytoreductive nephrectomy for clear cell mRCC in the cytokine immunotherapy era in the late 1990s. In the targeted therapy era, the practice of cytoreductive nephrectomy in nonclear and clear cell histology had been largely based on retrospective data, but a recent phase III trial showed that targeted therapy alone is noninferior to targeted therapy combined with cytoreductive nephrectomy, therefore, questioning the clinical benefit of cytoreductive nephrectomy in this context. However, this trial had excluded patient with nonclear cell histology. With the potential for checkpoint inhibitor combinations to achieve long-term complete durable response, cytoreductive nephrectomy is a subject of ongoing debate especially, in nonclear cell histology as those were excluded from prospective trials. Data are very sparse in nonclear histology. Although retrospective data favor the use of cytoreductive nephrectomy in nonclear cell mRCC, clinicians must carefully select patients and balance risks of surgery and delayed systemic therapy.

Autologous tumor cell vaccination combined with systemic CpG-B and IFN-\u03b1 promotes immune activation and induces clinical responses in patients with metastatic renal cell carcinoma: a phase II trial

In this study the toxicity and efficacy of an irradiated autologous tumor cell vaccine (ATV) co-injected with a class-B CpG oligodeoxynucleotide (CpG-B) and GM-CSF, followed by systemic CpG-B and IFN-α administration, were examined in patients with metastatic renal cell carcinoma (mRCC). A single-arm Phase II trial was conducted, in which patients with mRCC were intradermally injected with a minimum of three whole-cell vaccines containing 0.7–1.3 × 107 irradiated autologous tumor cells (ATC), admixed with 1 mg CpG-B and 100 µg GM-CSF, followed by bi-weekly s.c. injections with 8 mg CpG-B and s.c. injections with 6 MU IFN-α three times per week. Fifteen patients were treated according to the protocol. Treatment was well tolerated. Objective clinical responses occurred in three patients, including one long-term complete response. Disease stabilization occurred in another three patients. Positive delayed type hypersensitivity (DTH) responses to ATC were absent before treatment but present in 13 out of 15 patients during treatment. Immune monitoring revealed activation of plasmacytoid dendritic cells, non-classical monocytes and up-regulation of both PD-1 and CTLA4 on effector T cells upon treatment. Moreover, a pre-existing ex vivo IFN-γ response to ATC was associated with clinical response. ATV combined with systemic CpG-B and IFN-α is tolerable, safe, immunogenic and able to elicit anti-tumor responses in patients with mRCC. Immune activation and treatment-induced up-regulation of PD-1 and CTLA4 on circulating T cells further suggest an added benefit of combining this approach with immune checkpoint blockade [added]

Atypical Teratoid Rhabdoid Tumor of Spinal Cord: A Clinical Case

Background. Atypical teratoid rhabdoid tumor (AT/RT) of the central nervous system (CNS) is an aggressive malignant tumor, mostly affecting children younger than 3 years old. AT/RT is characterized by the deletion and/or mutation of gene SMARCB1/INI1, located in the long arm 22q11, leading to a loss of the nuclear expression of protein INI1, which may be detected by immunohistochemical assay with the anti-INI1 antibody. These tumors are mostly located in the brain, and their incidence in the spinal cord is very rare, with just a few publications on their clinical observations.Description of a Clinical Case. A clinical example of AT/RT in a two-year patient with the tumor located in the thoracic and lumbar spinal cord is described. The patient underwent surgical treatment consisting in the tumor resection and also chemoradiotherapy. Evaluation showed complete response. By the moment this paper was written, the duration of event-free survival of this patient was 27 months.Conclusion. This paper reviews the earlier published cases of spinal cord AT/RT, in which the most common location of the tumor was the cervical portion of the spinal cord. The maximum overall survival was 18 months, and the average overall survival was 9 months. In our clinical example, we demonstrate a long-term complete response to the multimodal treatment for AT/RT.

Cytotoxic Immune Response Can be Obtained Earlier in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Dasatinib Than with Other Tyrosine Kinase Inhibitors

Introduction: Generation of BCR-ABL fusion gene by reciprocal translocation of chromosomes 9 and 22 immortalizes hematopoietic stem cells by mechanisms such as activation of the JAK-STAT pathway, translational activation of BCL-XL, and inhibition of DNA repair, thereby leading to chronic myeloid leukemia (CML). Amazing improvement in the prognosis of CML has been achieved since the introduction of tyrosine kinase inhibitors (TKIs). Imatinib, a 1st-generation TKI, and dasatinib and nilotinib, 2nd-generation TKIs, are generally used for chronic phase (CP) CML as induction therapy. However, to date, no consensus about the cessation of TKIs in CP-CML patients has been obtained. We recently reported the case of a CP-CML patient with long-term complete molecular response (MR) after cessation of dasatinib, who has been maintaining memory CTLs with T cell receptor (TCR) clonality (Jo et al. Oncology Letters 15: 2935-2938, 2018). Here, we show that up-regulation of memory CTLs occurs early in dasatinib-treated patients compared with those treated with other TKIs.Methods: We examined the TCR V beta gene repertoire to analyze TCR clonality of CD8-positive T cells in TKI-treated CP-CML patients using flow cytometry.Results: Table 1 summarizes the data comparing patients treated with TKIs including dasatinib (Dasa group) and those treated with TKIs without dasatinib (non-Dasa group). Seven patients were treated with dasatinib only; 7, with imatinib only; 8, with multiple TKIs, including dasatinib; and 1, with multiple TKIs without dasatinib. The median age at first TKI administration was 57 years in the Dasa group and 69 years in the non-Dasa group. No significant statistical difference was observed in age at first TKI administration. The time of TCR clonality assay was significantly earlier in the Dasa group than in the non-Dasa group (P = 0.0013). There was no significant difference in the MR at the time of TCR clonality assay between the 2 groups. Figure 1 shows representative data of the TCR clonality assay of the patients in the non-Dasa group. We defined a TCR V beta gene percentage of 10% and above as being positive for monoclonality in this study. The time of analysis was at 116th month (Mo) after the 1st imatinib administration, and NK cell percentage was 30.2% at that time. TCR monoclonality was observed in neither effector CTLs (upper panel) nor memory CTLs (lower panel), although the patient had gained MR5. Figure 2 shows representative time-course data of the patients in the Dasa group. MR levels were MR4.5 (13th Mo), MR5 (16th Mo), and MR5 (19th Mo). Interestingly, memory CTL clonality with the TCR V beta 20 gene had already been observed in the 13th Mo, and it had been continuously observed in the 16th and 19th Mo. NK cell percentages were less than 24% throughout the observation period. Table 2 summarizes the CTL clonality assay results and NK cell percentages. There was no significant change in the NK cell percentages between the 2 groups. Although no statistical significance was observed in both effector and memory CTL clonality between the 2 groups, it is notable that approximately 73% and 87% positivity of effector and memory CTL clonality was observed in the Dasa group. Approximately 38% and 50% positivity of effector and memory CTL clonality was observed in the non-Dasa group, although the TKI exposure time for this group was significantly longer. Notably, the positive percentages of effector and memory CTL clonality in the non-Dasa group are quite similar to the overall probabilities of maintenance of deep MR reported in various imatinib-stop studies such as the STIM study (Mahon et al. Lancet Oncol 11: 1029-1035, 2010) and the TWISTER study (Ross et al. Blood 122: 515-522, 2013). These results suggest that acquisition of CTL clonality may correlate with treatment-free remission (TFR) in CP-CML patients treated with TKIs.Conclusions: Effector and memory CTL clonality was attained more rapidly and frequently in dasatinib-treated CP-CML patients than in patients treated with TKIs without dasatinib. There was no significant difference in the NK cell percentages. The positive percentages of CTL clonality resembled the percentages of TFR in various TKI-stop studies. These results suggest that the acquisition of CTL clonality may provide long-term remission and TFR to CP-CML patients and that cessation of TKIs should be considered in patients with clonal expansion of memory CTLs, irrespective of NK cells. [Display omitted] DisclosuresJo:Bristol-Myers Squibb: Honoraria.

Long-Term Complete Response of an Androgen Receptor-Positive Triple-Negative Metastatic Breast Cancer to Abiraterone Acetate.

Long-Term Complete Response of an Androgen Receptor-Positive Triple-Negative Metastatic Breast Cancer to Abiraterone Acetate.

Salvage regimens for pediatric patients with relapsed nasopharyngeal carcinoma.

There is no established salvage regimen for pediatric patients with relapsed nasopharyngeal carcinoma (NPC) and outcomes are dismal. We performed a multicenter retrospective review to determine outcomes after first salvage therapy for pediatric patients with relapsed NPC. Fourteen patients were treated with varied regimens. Two of the 14 patients received oxaliplatin-containing regimens and achieved a long-term complete response. Although definitive recommendations cannot be made based on outcomes for 14 patients who received varied regimens, we discuss justification for an oxaliplatin-containing regimen in combination with gemcitabine as a reasonable choice for first-line salvage therapy for pediatric patients with relapsed NPC.