ALBERT

Description: Classic Hodgkin Lymphoma (cHL) is a germinal center derived lymphoma with 8,500-9,000 new cases/year diagnosed in the US. Despite 90% stage I cHL patients can respond to current systemic therapy, this drops to 60%, when diagnosed in advanced stages. Furthermore, 20-30% of diagnosed patients, would be refractory or would relapse and have a poor prognosis. Refractory and relapsed disease (RRD) is currently the challenge when treating cHL patients. There is no specific therapy to offer rather than rescue chemotherapy schemes, which fails in 50% of the cases and associates with high risk severe toxicity. This highlights the need to deeper understand the cHL molecular biology, the screening for molecular markers suitable to identify the risk of refractory and relapse disease and specific therapeutic directed-targets. We have previously reported that the alternative NFkB pathway, mediated by Rel-B and NIK (NFkB Inducing Kinase), plays an important role in cHL survival. Its constitutive activation sustains high BCL2 expression levels and seems to be involved in the RRD. BCL2 was found as a specific Rel-B target gene in cHL cells by ChIP-Seq (Chromatin Immunoprecipitation sequencing) and expression arrays. BCL2 exogenous expression was enough to partially rescue the death induce in cHL cells, which highlight the relevance of this alternative NFkB pathway target gene. Since the BCL2 data was obtained in human cHL cell lines established from patients with refractory and relapsed disease, we decided to analyze whether mediators of this pathway and BCL2 could be useful as prognosis markers and would represent potential targetable factors in both refractory and relapsed disease. We analyzed NIK and BCL2 citoplasm expression in Hodgkin Reed-Sternberg cells (HRS) in the lymph node biopsies of 113 cHL naïve of therapy patients by inmunohistochemistry [52 female Md age and (range) 36 (6-88), 61 male 40.7 (9-78)]. The follow-up period range from 6 to 136 months. The univariate analysis showed no correlation between NIK or BCL2 expression and the prognosis clinical and pathological parameters, including the PET Scan indicated at the end of the first line treatment, neither the molecular markers routinely assayed. The statistical significance was maintained in multivariate analysis (Logistic and Cox Regression p=0.01). NIK expression did not associate with prognosis but the BCL2 expression level correlated with lack of response to conventional therapy and both early and late disease progression. The survival analysis, using the Kaplan-Meir curves, showed that patients with ≥60% positive HRS cells had a shorter disease-free survival (DFS) [Log Rank Test (Mantel Cox) p=0.002] and a reduced overall survival (OS) [Log Rank Test (Mantel Cox) p=0.02]. L1236, U-H01, KM-H2, SUPDH1 and L540, human cHL cell lines that express BCL2 protein, were sensitive to venetoclax, a specific BCL2 inhibitor. The drug induced a cell cycle arrest in S-Phase when treated with 1uM each 24 hours during 10 days, as compared to wild type cells and cells treated with the vehicle. In summary, we found that the alternative NFkB pathway plays a role in the refractory and relapsed classic Hodgkin Lymphoma disease, being BCL2 one of its key downstream target genes. BCL2 can be used as a prognosis marker determined by routine immunohistochemistry at diagnosis of the primary disease. BCL2 expression correlated with refractory disease to first line conventional therapy and disease progression. Based on the venetoclax effect in cHL cell lines we believe BCL2 directed-therapy in cHL should be considered in the subgroup of cHL patients that express this protein in ≥60% HRS cells in the lymph node biopsy performed at diagnosis. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: venetoclax used to specifically block BCL2.

Description: Abstract 4982 Lenalidomide is an immunomodulatory agent that stimulates T-cell activation, enhances natural killer cells and inhibits cytokines, as tumor necrosis factor-alpha. It is FDA-approved for use in both transfusion-dependent myelodysplastic syndrome, especially 5q deletion syndrome and refractory and relapsed multiple myeloma. The known side effects are myelosuppression, diarrhea/constipation, fever, fatigue, rash and thromboembolism, while pulmonary complications are rarely reported. We present a patient with myelodysplastic syndrome on lenalidomide with acute pulmonary toxicity. A 63-year-old Caucasian man was diagnosed with low-intermediate risk myelodysplastic syndrome with 5q deletion after presenting with anemia and thrombocytopenia. He was started on lenalidomide at 21mg daily dose but after 5 days began to develop dyspnea on exertion, cough and fever. He was admitted for treatment of community acquired pneumonia. Physical examination revealed a middle aged man in respiratory distress. Oxygen saturation on room air was 86%. Chest examination revealed dry crackles. Heart sounds were regular without murmurs or gallops. Laboratory tests revealed hemoglobin of 8.6g/dl, normal white count at 10,000 and platelets of 7,000/uL. BNP and echocardiogram were normal and chest radiography was initially unremarkable. He was started on antibiotics but developed respiratory failure requiring endotracheal intubation and mechanical ventilation. CT scan of the chest showed diffuse interstitial reticulonodular opacities most prominent at the apices with scattered ground glass attenuation. Cultures from blood, sputum, urine and stool and brochoalveolar lavage did not reveal an infectious source. Broad spectrum antibiotics and antifungals were withheld. Clinical and radiologic improvement was noted after withdrawal of lenalidomide and initiation of steroids. He was persistently transfusion-dependent hence lenalidomide was reintroduced. Within 6 days of lenalidomide, respiratory symptoms recurred. He later improved after withdrawal of the offending drug. Our myelodysplastic patient developed acute respiratory failure after lenalidomide introduction which improved with steroids and drug withdrawal. He had symptom recurrence after reintroduction of lenalidomide. The exposure history, clinical and radiological examination, positive challenge test with exclusion of other etiologies support the diagnosis of lenalidomide-induced hypersensitivity pneumonitis. This is the third reported case of lenalidomide-induced hypersensitivity pneumonitis and it is likely that this entity is underdiagnosed due to concurrent steroid use especially in myeloma patients. Clinicians should be aware of this potential complication in patients who present with fever, hypoxemia and diffuse pulmonary infiltrates unresponsive to broad spectrum antibiotics as this disease is reversible if diagnosed early. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1476 Ad-ISF35 is a replication-defective adenovirus (Ad) vector that encodes ISF35, which is a potent immuno-stimulatory CD40 binding protein designed to maximize stable, high-level cell-surface expression of this molecule. ISF35 can induce expression of costimulatory and death receptor molecules on chronic lymphocytic leukemia (CLL) cells in vitro and in vivo. Ad-ISF35 has shown to be safe and to have potential activity in two clinical studies in CLL patients, one using infusions of autologous CLL cells trasduced ex-vivo with Ad-ISF35 and the second one using a single intranodal injection of Ad-ISF35. From this second study we have observed that the maximum tolerated intranodal dose (MTD) was 3.3 × 1010 viral particles (vp) due to development of asymptomatic and transient hypophosphatemia, SGOT/AST elevation and neutropenia in some patients treated with higher doses. Using this MTD dose (3.3 × 1010 vp), we designed a clinical study to evaluate the toxicity and efficacy of repeat doses of intranodal Ad-ISF35 administration in CLL patients. Ten patients with median age of 66 years (range 56–74, 80% male and 20% female), with progressive CLL (Rai stage III and IV) and median leukemia-cell doubling times of 6 months participated in this repeat dose intranodal administration study involving up to six biweekly injections with a fixed dose of 3.3 ×1010 vp. Intranodal Ad-ISF35 injections were done into pathologically enlarged lymph nodes accessible by palpation using ultrasound guidance. Repeat dose intranodal administration of Ad-ISF35 was well tolerated by the majority of patients. The median number of injections was 5. One patient developed transient and asymptomatic Grade III hyponatremia after injection #4 considered to be a dose-limiting toxicity (DLT). No dose adjustments were required in any of the patients and we have not observed cumulative dose effect or long-term toxicities after a median follow up of 14 months. Other adverse events included erythema, swelling and/or pain at the site of injection and “flu-like symptoms”, which occurred primarily during the first 24 hours after each injection and were self-limited. The majority of patients experienced 〉50% reduction in leukemia cell counts (70% of patients), lymphadenopathy (80% of patients) and/or splenomegaly (70% of patients) during the course of treatment. Response assessment based on IW-CLL-08 criteria showed and overall response rate of 30% with 3 patients achieving a partial response, 4 patients with stable disease and 3 patients with disease progression. Although we have no evidence of Ad-ISF35 vector expression beyond the injected lymph node, we observed upregulation of death receptors, immune costimulatory molecules, and pro-apoptotic proteins in the circulating, non-transduced CLL cells of the treated patients suggesting a bystander effect. Cytokine expression analysis in the sera of treated patients showed increased levels of interferon-gamma and interleukin-6 beginning 8 hours after injection. In addition, we observed evidence of antibody production against Ad-ISF35 with the ability in some cases to neutralize vector transduction in vitro. However, we did not see antibody formation against human CD154. In summary, we found that repeat dose Ad-ISF35 intranodal administration via direct injection in patients with CLL was well tolerated and had systemic biologic and clinical activity that appears to be mediated by the effect of non-transduced bystander cells. These data suggest that intranodal administration of Ad-ISF35 may be safe and potentially effective in the treatment of patients with CLL or other B-cell lymphomas. Disclosures: Kipps: Memgen, LLC: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of lymphoma in the world and corresponds to a heterogeneous entity, both from the clinical and molecular point of view, being its prognosis of survival very variable The IPI and the NCCN-IPI are powerful risk-stratification tools in patients with DLBCL. Although the IPI risk score is widely used, it doesn't discriminate very high risk patients. In 2014 the NCCN-IPI was published. It has shown a better discrimination of these patients in Asia, Europe and USA. GELL is a recently formed group of study in lymphomas from Latin America that includes eleven countries. The aim of this study was to validate whether the NCCN-IPI is of prognostic value in Latin-American patients with DLBCL. Methods: We included patients with a diagnosis of DLBCL treated at different institution between 2012-2013. IRB approval was obtained before the collection of the data. Pathological samples were reviewed at each participating institution to confirm the diagnosis. Pertinent clinical data were collected through chart review and are presented using descriptive statistics. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox proportional-hazard regression models were fitted to evaluate hazard ratio (HR) for overall survival (OS). Results: A total of 329 patients with the diagnosis of DLBCL were included in this analysis. The median age at diagnosis was 64 years (range 18-83 years) with a slight female predominance (54%). Clinically, 59% of patients were 60 or older, 34% presented with ECOG 〉1, 29% with elevated serum LDH, and 70% with extranodal disease; 49% had stage I/II and 51% had stage III/IV. The IPI score distribution was low-risk in 36% of patients, low-intermediate in 25%, high-intermediate in 22% and high-risk 17%. The NCCN-IPI score distribution was low risk in 17%, low-intermediate in 42%, high intermediate in 30% and high risk in 11%. 89% of patients received standard R-CHOP, 2% received R-miniCHOP, and 9% received other regimens. The overall response rate was 83%; 69% had complete response and 14% had partial response. The 5-year overall survival (OS) rate was 65%. DLBCL patients with low, low-intermediate, high-intermediate and high risk NCCN-IPI had 5-year OS rates of 89%, 71%, 55% and 38%, respectively (p

Description: Despite 90% stage I Hodgkin Lymphoma (HL) patients can respond to current systemic therapy, this drops to 60%, when diagnosed in advanced stages. Nevertheless and independently of the lymphoma stage, the real challenge when treating these patients, is the refractory and relapsed disease. There is no molecular biomarker to identify patients that would be non-responsive to conventional treatment or that would relapse. Furthermore, rescue chemotherapy schemes for refractory and relapsed patients, associate with acute and late toxicity high risk. This highlights the need to deeper understand the HL molecular biology and the screening for predictive biomarkers as well as potential therapeutic directed-targets. We have previously reported that HL relies on the alternative NFkB pathway, mediated by RelB and NIK, to survive. Depletion of either RelB or NIK by shRNAs or pharmacological NIK inhibitors induce HL cell death. ChIP-Seq analysis uncovered RelB target genes showing RelB bound to BCL2 promoter. A significant downregulation of BCL2 mRNA and protein levels, following RelB or NIK knockdown was observed, indicating that RelB regulates BCL2 expression in human HL cell lines. Our molecular studies suggested that NFkB alternative pathway constitutive signaling could at least partially explain the non-responding HL cases. We aimed to analyze whether mediators of this pathway could be useful as predictive biomarkers and would represent potential targetable factors in both refractory and relapsed patients. We analyzed NIK and BCL2 citoplasm expression in Hodgkin Reed-Sternberg cells (HRS) in lymphatic node biopsies of 96 patients by inmunohistochemistry [50 female Md age and (range) 59 (6-82), 46 male 42 (9-78)]. The univariate analysis showed no correlation between NIK or BCL2 expression and the prognosis clinical and pathological parameters, neither the molecular markers routinely assayed. A positive correlation was found between NIK and BCL2 expression (p=0.01). NIK and BCL2 correlated with lack of response to conventional therapy and both early and late disease progression. The analysis of survival, applying the Kaplan-Meier Curves, showed 〉 60% NIK positive HRS cells associated with shorter Disease Free Survival (DFS) [Log Rank Test (p=0.000)] and predicted overall survival (OS) as well [Log Rank Test (p=0.01)]. Furthermore, 〉 60% BCL2 positive HRS cells correlated with poor prognosis in terms of OS [Log Rank Test (p=0.002)]. The statistical significance was maintained in the multivariate analysis [Cox Regression and Logistic Regression (p=0.001)]. NIK and BCL2 performed successfully as useful predictive markers to identify refractory or risk of relapse HL patients at diagnosis. They represent attractive molecules to further analyse their potential as directed-therapy targets, since we have already reported that HL is sensitive to NIK inhibitors and BCL2 blockers have already been approved for clinical use in other hematological pathologies. Disclosures Zerga: Bristol Myers Squibb: Other: Conference fees; Janssen: Other: Conference fees; Roche: Other: Conference fees; Takeda: Other: Conference fees.

Description: Introduction: Diffuse large B-Cell Lymphoma (DLBCL) is the most frequent subtype of lymphoma in the world. The IPI score is a powerful risk-stratification tool in patients with DLBCL. The neutrophil-to-lymphocyte ratio (NLR) has shown to be prognostic in patients with DLBCL in Asia, Europe and USA. The GELL is a recently formed group for the study of lymphomas in Latin America composed by large institutions from eleven countries. The aim of this study was to evaluate whether the NLR is a prognostic factor in Latin American patients with DLBCL. Methods: We included patients with a pathological diagnosis of DLBCL who were diagnosed and treated at our institution between 2012-2013. IRB approval was obtained prior to research, and pathological samples were reviewed by hematopathologists at each of the participating institutions to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review and are presented using descriptive statistics. The NLR was calculated by dividing the absolute neutrophil by the absolute lymphocyte count and dichotomized in NLR≥4 and NLR1, 29% had elevated LDH, and 70% had extranodal disease; 49% had early stage and 51% had stage III and IV. The IPI score was low risk in 36%, low-intermediate in 25%, high intermediate in 22% and high risk in 17%. 41% of patients had NLR ≥4. 89% of patients received standard R-CHOP, 2% received R-miniCHOP and 9% received other regimens. The overall response rate as 83%; 69% had complete response and 14% had partial response. The median follow-up for the entire group was 5 years (95% CI 4.9-5.4 years). The 5-year overall survival (OS) rate for the entire group was 65%. The 5-year OS rates for patients with NLR ≥4 and

Description: Erythrocytic malaria parasites degrade hemoglobin as a source of amino acids for parasite protein synthesis. Cysteine proteinase inhibitors have been shown to block the hydrolysis of globin by cultured parasites, indicating that a malarial cysteine proteinase is required for this process. In the present study, we have evaluated the role of parasite proteinases in earlier steps of hemoglobin degradation, namely the disassociation of the hemoglobin tetramer and the separation of heme from globin. Hemoglobin did not spontaneously denature or release heme under the pH and reducing conditions of the malarial food vacuole, suggesting that parasite enzymatic activity is necessary for early steps in hemoglobin degradation. The incubation of cultured parasites with cysteine proteinase inhibitors inhibited the denaturation of hemoglobin and the release of heme from globin. These results suggest that, in addition to its role in globin hydrolysis, a malarial cysteine proteinase participates in the dissociation of the hemoglobin tetramer and the release of heme from globin. Thus, the malarial cysteine proteinase is a promising target for antimalarial chemotherapy.

Description: Abstract 1421 More than 2 million Americans use cocaine each month. Levamisole is a veterinary antihelminthic agent that has been used as a cutting agent in cocaine and adds bulk to powdered cocaine. It has been used for the treatment of colon cancer, rheumatoid arthritis and nephrotic syndrome. According to the Drug Enforcement Administration (DEA) as of July 2009, 69% of seized cocaine lots coming into the United States contained levamisole as an added agent. Levamisole has recently been reported to cause neutropenia in cocaine abusers. We report a case of a severe cutaneous necrotizing vasculopathy, agranulocytosis with acquired protein S deficiency caused by tainted cocaine in an active abuser. A 44-year-old active cocaine abusing woman presented with a day of acute worsening cutaneous lesions, subjective fever and arthralgias. She last inhaled three bags of cocaine the day prior to admission. On examination, she had multiple tender palpable purpuric plaques with central necrosis on her thighs, lower extremities, chest, abdomen, arms, and bilateral ear helices. Urine toxicology screen was positive for cocaine. Laboratory data showed neutropenia of 1.4 × 103/uL with mild anemia (haemoglobin 12g/dl) and normal platelet count. She had anemia of chronic disease with negative Coombs test. She also has normal kidney and liver functions. Vasculitides and rheumatological workup showed positive antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase-3 (PR-3) and myeloperoxidase (MPO) but negative for ANA or rheumatoid factor and normal complement levels. Assays for syphilis, hepatitis B and C, and the human immunodeficiency virus were negative. A skin biopsy showed small vessel thrombo-vasculopathy with organizing thrombus and mixed cell infiltrate. Subsequent workup for hypercoagulable states revealed a positive lupus anticoagulant and a low protein S activity. The patient was treated with steroids. Her skin lesions and neutropenia improved gradually in two weeks.Figure 1.Palpable purpuric plaques on bilateral lower extremities.Figure 1. Palpable purpuric plaques on bilateral lower extremities.Figure 2.Necrotic ear helix.Figure 2. Necrotic ear helix.Figure 3.Skin biopsy showing small vessel thrombovasculopathy, organizing thrombus and mixed cell infiltrate.Figure 3. Skin biopsy showing small vessel thrombovasculopathy, organizing thrombus and mixed cell infiltrate. The acute onset of necrotic skin lesions following cocaine use, ANCA positivity, histopathology and neutropenia strongly suggest levamisole-induced vasculopathy. Although levamisole levels were not obtained, exposure from cocaine contamination is very likely. Levamisole is known to have immunostimulating effects with the production of autoantibodies like ANCA. Life-threatening agranulocytosis and a positive lupus anticoagulant have been reported in a few cases of prolonged levamisole use. The pathogenesis of agranulocytosis is hypothesized to either be a direct toxin effect or immune-mediated. Lupus anticoagulant has also been reported to cause a similar pattern of cutaneous necrosis. Clinicians should be aware of this kind of clinical presentation in active cocaine abusers and consider it as a significant emerging public health problem. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4638 High-dose methylprednisolone (HDMP) and the fully human monoclonal anti-CD 20 Ofatumumab each can produce partial responses in CLL, even though complete remissions are not often observed following treatment with either agent alone. Previously we have reported that the combination of Rituximab and HDMP is an effective non-myelosuppressive treatment combination for previously untreated CLL patients as well as in patients that are fludarabine refractory. We report here our single institution experience of treatment using the combination of HDMP and Ofatumumab in CLL patients that were not considered to be good candidates for chemotherapy treatment due to comorbidities, poor performance status, profound cytopenias or because refractory status to fludarabine and/or alemtuzumab. Eight patients with progressive, symptomatic CLL were treated with HDMP 1 g/m2 IV daily × 3 every 28 days for three consecutive cycles, and ofatumumab administered based on package insert instructions (300 mg dose # 1 followed by 11 doses of 2,000 mg over a 6 month period) along with prophylactic antimicrobial therapy. The main objectives were to determine the safety, toxicity and clinical efficacy of this regimen. All of the patients were males with a median age of 69 years (range 49–78). The median of prior treatments was 4.5 including 4 patients that have received previously HDMP and rituximab and two patients that underwent matched unrelated donor stem cell transplant. All patients have been previously treated with rituximab, 75% of the patients failed or were intolerant to fludarabine and/or aletuzumab and 88% had high-risk disease by the modified Rai classification. Most of the patients had bulky disease with median lymph node product of 42 cms2 and median splenomegaly of 6. 5 cm (range 0–17) below the left costal margin. The median lymphocyte count was 28,000 cells/mm3. 75% of the patients had high-risk prognostic markers including unfavorable cytogenetics, unmutated IgVH region genes or high expression levels of ZAP-70. All patients completed the planned therapy with no major side effects or toxicities. There was no evidence of marrow suppression and even patients with pancytopenia improved their peripheral blood counts with this salvage regimen. During treatment patients experience significant decrease in peripheral white blood cell counts, increase in hemoglobin, elevation of platelets and a dramatic reduction in lymphadenopathy and splenomegaly. Response assessment based on the IW-CLL 2008 criteria showed that the overall response rate was 50% (4 partial remissions), 25% of patients had stable disease and the remainder showed progressive disease. Overall, these data suggest that the combination of HDMP and Ofatumumab is a safe and effective salvage regimen for high-risk CLL patients that otherwise were not candidates for additional treatment. The response rates observed for the combination of HDMP and Ofatumumab in this group of patients appear to be favorable with the majority of patients achieving a response to therapy or experiencing disease stabilization. Moreover, HDMP and Ofatumumab treatment was not associated with bone marrow suppression, which is a major limiting factor for treatment administration, making this regimen a potential valid alternative for high-risk CLL patients. Additional clinical studies of this combination are warranted. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1472 Background: Chronic lymphocytic leukemia (CLL) cells with del(17p) typically have loss of functional P53, rendering them refractory to chemotherapeutic agents. However, del(17p) CLL cells activated by CD40L (CD154) are induced to express pro-apoptotic factors that re-sensitize cells to the cytotoxic activity of P53-dependent drugs, such as fludarabine (F-ara-A). Chemotherapy re-sensitization is mediated in part by induction of p73, a p53-related transcription factor. To examine whether a CD154-based therapeutic strategy can be developed in vivo for del(17p) and/or fludarabine refractory CLL, a phase 1b clinical study evaluating an autologous cellular gene immunotherapy is being conducted. Autologous CLL cells transduced ex vivo with a replication defective adenovirus vector encoding a membrane-stable, re-engineered form of CD154 (Ad-ISF35) are administered, followed by standard courses of FCR in subjects with high-risk fludarabine refractory and/or del(17p) CLL. Methods: Subjects with fludarabine refractory and/or del(17p) receive three IV doses (one dose every two weeks) of 3×108 autologous CLL cells that have been transduced ex vivo with Ad-ISF35. Two weeks following the third dose of Ad-ISF35-transduced cells, subjects receive standard monthly cycles of fludarabine, cyclophosphamide and rituximab (FCR). Study endpoints include analysis of safety and efficacy. Correlative analyses are conducted for evidence of drug re-sensitization, regulation of apoptotic pathways, cytokine analysis, and humoral immune responses to the adenovirus vector and ISF35 transgene. Results: To date, four patients have completed treatment. Two patients have achieved a compete response, one of them without detectable minimal residual disease (MRD) by sensitive multiparameter flow cytometry of marrow mononuclear cells after completion of treatment. These responses have been durable after a median follow up of 18 months. One patient achieved a partial response with complete resolution of lymphocytosis, lymphadenopathy and splenomegaly, but residual CLL in the bone marrow. The remaining patient had progressive disease despite an initial response to both infusion of Ad-ISF35-transduced cells and FCR chemoimmunotherapy. Infusion of Ad-ISF35 transduced cells has been well tolerated. Overall, the most common adverse events have been transient fever, malaise and fatigue associated with infusion of Ad-ISF35-transduced cells and cytopenias after treatment with FCR. Prior to ISF35 treatment, CLL cells from patients were resistant to F-ara-A induced apoptosis (IC50 〉 10μM). However, one day following the first infusion of Ad-ISF35-transduced CLL cells, patient cells became sensitive to F-ara-A (IC50 0.3–1 μM). In addition, pro-apoptotic factors, including Bid, DR5, CD95, and P73 were induced in the non-transduced “bystander” CLL population following ISF35 infusion. These pro-apoptotic effects persisted ≥ 2 weeks following IV infusion. The sera from treated patients showed increase in IL-6 and IFN-γ after infusion of Ad-ISF35 transduced CLL cells. Despite evidence of anti-adenovirus antibody responses in the treated patients, there was no detectable anti-human CD154 production before or after ISF35 treatment. Conclusions: The results indicate that Ad-ISF35-cell-gene therapy can sensitize P53-deficient CLL to “P53-dependent” cytotoxic agents in vivo, allowing for effective and durable clinical responses. These data are very encouraging and suggest that this unique chemoimmunotherapy re-sensitization strategy could offer a valuable treatment option for patients who otherwise would be resistant to standard forms of therapy. Disclosures: Cantwell: Memgen: Employment. Kipps:Memgen, LLC: Membership on an entity's Board of Directors or advisory committees.