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Abstract BACKGROUND 331 glioblastoma patients were immunized with autologous dendritic cells (DCs) pulsed with autologous tumor cell lysate or placebo in a Phase 3 clinical trial. Immunization with the pulsed DCs was associated with extended overall survival in both newly diagnosed and recurrent disease. Objective: To characterize T cell responses and T cell response dynamics in patients immunized with autologous dendritic cells pulsed with autologous tumor cell lysate. METHODS we performed T cell receptor sequencing on peripheral blood mononuclear cells from both newly diagnosed and recurrent glioblastoma patients that were treated with the pulsed DCs. Timepoints from both before and after immunization were compared to understand T cell response dynamics. RESULTS Expansion of several hundred new T cell clones as well as more than 700 previously detected T cell clones was detected over time in both newly diagnosed and recurrent GBM patients who were treated with the pulsed DCs. Investigation of the dynamics of the response demonstrated that further expansion was triggered by ongoing immunizations. Correlations between T cell response data and clinical outcomes are ongoing. CONCLUSION Immunization with autologous DCs pulsed with autologous tumor cell lysate induces broad spectrum immune responses in patients with glioblastoma.

Key Points Question Is treatment with autologous tumor lysate-loaded dendritic cell vaccination (DCVax-L) associated with improved overall survival (OS) for patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) compared with standard of care (SOC)? Findings In this phase 3 nonrandomized controlled trial of 331 patients, patients with nGBM receiving DCVax-L had a median OS of 19.3 months from randomization (22.4 months from surgery), while contemporaneous, matched external control patients treated with SOC had a median OS of 16.5 months from randomization; for patients with rGBM, median OS was 13.2 months from relapse in the DCVax-L group vs 7.8 months in the external control cohort. Meaningful increases in the long-term tails of the survival curves in both nGBM and rGBM were also observed. Meaning In this study, adding DCVax-L to SOC was associated with a clinically meaningful and statistically significant improvement in median OS for patients with both nGBM and rGBM compared with matched, contemporaneous external controls.

Abstract BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

Background Glioblastoma (GBM) is an incurable form of brain cancer with a high mortality rate in which multiple treatment attempts over the past decade have proven unsuccessful at extending survival. Early stage data have suggested that immunization against tumor cell antigens may be effective in GBM. In this Phase 3 study we aimed to assess whether autologous dendritic cells (DCs) loaded with autologous tumor cell lysate, is able to improve survival in these patients. Methods We conducted a randomized, double-blind, placebo-controlled international Phase 3 clinical trial with autologous tumor lysate-loaded DCs (DCVax-L) in 331 patients with histologically confirmed newly diagnosed GBM. Following surgery and chemoradiation, patients were randomized 2:1 to receive temozolomide plus DCVax-L or temozolomide plus placebo (i.e., autologous PBMC). Eligibility criteria included an intent for significant tumor resection (not biopsy only), sufficient doses of DCVax-L manufactured for 5 or more immunizations, and no radiographic evidence of apparent disease progression at the end of chemoradiation. A crossover option allowed all patients to receive the autologous vaccine at the time of disease progression. As a result, 90% of the randomized patients received DCVax-L at some point during their participation in the trial. Study subjects received immunizations with 2.5 million DCs or placebo at days 0, 10 and 20, followed by immunizations at months 2, 4, 8, 12, 18, 24 and 30. All subjects were assessed for progression-free survival(PFS) and overall survival (OS). This trial is registered with clinicaltrials.gov, number NCT00045968. Trial Registration The study was registered as NCT00045968 Ethics Approval The study was approved by all applicable Institutional Review Boards or Ethics Committees

Abstract Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice. Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection. Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (P < 0.01). Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845–56. ©2018 AACR.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.

Abstract Background: Activated, autologous dendritic cells (aaDC) can be used to induce anti-tumor immune responses. A unique method of applying aaDC is through intratumoral injection, where the tumor cells serve as the source of antigen required for an adaptive anti-tumor response. A local effect may also occur as a result of cytokine production by the injected DC which makes the tumor more susceptible to a pre-existing or an induced immune attack. Methods: Forty patients with locally advanced or metastatic solid tissue cancers were treated in a dose escalation trial in which aaDC were injected percutaneously under image guidance into a single tumor. Subjects had a median of 3 tumors (range 1 - 5) and had received an average of 3.1 prior treatments. To generate the aaDC, autologous monocytes were converted ex vivo into DC which were then activated. All batches of DC were released based on pre-specified criteria which included immunophenotyping and a T cell-stimulation assay, as well as sterility and endotoxin levels. Cytokine levels produced by the activated DC during manufacturing were measured and patient outcomes were correlated to these expression levels. Results: All three doses levels were well tolerated. The main adverse events related to treatment were grade 1 and 2 fevers. Twenty-one patients achieved stable disease (SD) 8 weeks after initiating treatment, and this was found to correlate with survival (p = 0.01). Levels of certain cytokines, such as such IL-8 and IL-12 p40, and TNFα were substantially elevated in vitro and IL-8 and IL-12 p40 production were predictive of survival (p = 0.001 and p = 0.008 resp.). TNFα levels also correlated with SD at week 8 (p = 0.01). More than 70% of patients tested were found to have significant T cell responses, and/or de novo or significantly enhanced PD-L1 expression in the tumor post treatment, with a trend towards improved survival (p = 0.1). Conclusions: Study outcomes such as stabilization of disease and survival correlated with high DC cytokine levels, in the absence of meaningful toxicity. The DCVax treatment may be mediated through direct cytotoxic effects, as well as modulation of the tumor microenvironment to increase tumor infiltration by T cells, and attraction of inflammatory cells to the tumor. The development of PD-L1 expression likely reflects an induced immune response. Citation Format: Vivek Subbiah, Ravi Murthi, Robert Prins, Kyle Hendricks, Chitra Hosing, Lori Noffsinger, Mary McGuire, Robert Brown, Aung Naing, David Hong, Siqing Fu, Anthony Conley, Indreshpal Kaur, Sarah Campion, Marnix Bosch. Cytokine production by intratumorally administered activated dendritic cells correlates with survival in a Phase I clinical trial in diverse cancers [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B005.

Meeting abstracts Dendritic cells (DC) are proficient in initiating adaptive immune responses, through the uptake and subsequent presentation to the immune system of antigenic compounds. In preclinical studies, activated DC (aDC; DCVax®-Direct) were shown to be superior to immature DC in clearing

Abstract Background The survival rate in recurrent Glioblastoma multiforme (rGBM) patients has not meaningfully changed in the past several decades. We have treated two cohorts of rGBM patients, one consisting of patients with early progression, and one of patients with progression following several cycles of adjuvant temozomolide chemotherapy, with autologous dendritic cells pulsed with autologous tumor cell lysate (DCVax®-L). Such treatment is intended to activate the immune system against the tumor cells, so that the ensuing immune attack may delay progression and time to death. Methods Disease progression in patients with GBM was determined through MRI. Progression needed to be determined by independent review on 2 consecutive scans for early progressor classification to avoid enrolling patients with pseudoprogression. Assessment of progression was done using modified RANO criteria. Results Nineteen (19) patients diagnosed with GBM were determined to have recurrence immediately following radiation therapy with concomitant temozolomide chemotherapy. Median overall survival in this cohort from initial GBM diagnosis is 15.1 months (95% CI: 10.5-17.2), and the range is 8.1->31 months. A literature search revealed 6 publications with comparable populations of patients. The table below demonstrates that these patients typically have a life expectancy of 8-10 months. Reference (n)PopulationMedian Survival (95% CI)DCVax-L (19)PD post RT+chemo, confirmed 2 months later15.1 months (10.5 - 17.2)Brandes et al. 2008 (18)PD at 4 weeks pos RT+chemo, confirmed after two more tmz cycles10.2 months (n.a.)Roldan et al. 2009 (10)PD at 4-6 weeks post RT+chemo, confirmed after ≥1 more tmz cycle(s)9.1 months (4.9 - 19.1)Kang et al. 2010 (10)PD at 2 consecutive scans post RT+chemo10.8 (n.a.)Sanghera et al. 2010 (29)PD at 2 consecutive scans within 8 weeks post RT+chemo8.3 months (n.a.)Gunjur et al. 2011 (27)PD at 2 consecutive scans within 3 months post RT+chemo, or clinical deterioration10.4 months (n.a.)Linhares et al. 2013 (13)PD at 2 consecutive scans within 3 months post RT+chemo9.0 months (3.7 - 14.3) A second cohort of patients with rGBM consisted of 8 patients with recurrence following several adjuvant temozolomide treatment cycles. Median OS for these patients is 14.7 months from the time of surgery for first recurrence. The comparator for this cohort is derived from Friedman et al. (2009), who reported mOS of 8.7-9.3 months from the time of first recurrence for rGBM patients treated with Bevacizumab with or without Irinotecan. Results and Conclusion These results suggest that treatment with DCVax-L can extend survival by 5 months or more in patients with rGBM. Citation Format: Marnix Bosch, Robert Prins, Linda Liau. Treatment with tumor lysate-pulsed autologous dendritic cells prolongs survival in patients with recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2491. doi:10.1158/1538-7445.AM2015-2491

Background Recurrent glioblastoma multiforme (rGBM) is a life threatening condition, with a mortality rate of approximately 100%. Despite recent advances in therapy, the survival rate in rGBM patients has not meaningfully changed in the past several decades. We have treated two cohorts of rGBM patients, one consisting of patients with early progression, and one consisting of patients with progression following several cycles of adjuvant temozomolide chemotherapy, with autologous dendritic cells pulsed with autologous tumour cell lysate (DCVax®-L). Such treatment is intended to activate the immune system against the tumour cells, with the expectation that the ensuing immune attack may delay progression and time to death. Aim To determine survival characteristics of patients with rGBM who are treated with DCVax-L. Methods Disease progression in patients with GBM was determined through magnetic resonance imaging. Progression needed to be determined by independent review on two consecutive scans for early progressor classification to avoid enrolling patients with pseudoprogression. Assessment of progression was done using modified RANO criteria. Results Nineteen (19) patients diagnosed with GBM were determined to have rapid recurrence following radiation therapy with concomitant temozolomide chemotherapy. The life expectancy for such patients is typically poor, and they were provided the DCVax-L treatment as part of a compassionate use approach in parallel to ongoing late stage clinical trials. Median overall survival in this cohort from initial GBM diagnosis is 15.1 months (95% confidence interval (CI): 10.5–17.2), and the range is 8.1–>31 months. A literature search revealed six publications with comparable populations of patients (Brandes et al., 2008; Roldan et al., 2009; Sanghera et al., 2010; Kang et al., 2010; Gunjur et al., 2011; Linhares et al., 2013). The table below demonstrates that these patients typically have a life expectancy of 8–10 months. Reference (n) Population Median Survival (95% CI) DCVax-L (19) post RT+chemo, confirmed 2 months later 15.1 months (10.5–17.2) Brandes et al. (2008) (18) PD at 4 weeks pos RT+chemo, confirmed after two more tmz cycles 10.2 months (n.a.) Roldan et al. (2009) (10) PD at 4–6 weeks post RT+chemo, confirmed after ⩾ 1 more tmz cycle(s) 9.1 months (4.9–19.1) Kang et al. (2010) (10) PD at two consecutive scans post RT+chemo 10.8 (n.a.) Sanghera et al. (2010) (29) PD at two consecutive scans within 8 weeks post RT+chemo8.3 months (n.a.) Gunjur et al. (2011 (27) PD at two consecutive scans within 3 months post RT+chemo, or clinical deterioration 10.4 months (n.a.) Linhares et al. (2013) (13) PD at two consecutive scans within 3 months post RT+chemo 9.0 months (3.7–14.3) A second cohort of patients with rGBM consisted of eight patients with recurrence following several adjuvant temozolomide treatment cycles. Median overall survival (OS) for these patients is 14.7 months from the time of surgery for first recurrence. The comparator for this cohort is derived from Friedman et al. (2009), who reported mOS of 8.7–9.3 months from the time of first recurrence for rGBM patients treated with Bevacizumab with or without irinotecan. Results and conclusion The results obtained in two cohorts of patients with rGBM suggest that treatment with autologous DC pulsed with autologous tumour cell lysate can extend survival by 5 months or more. Recurrent glioblastoma multiforme (rGBM) is a life threatening condition, with a mortality rate of approximately 100%. Despite recent advances in therapy, the survival rate in rGBM patients has not meaningfully changed in the past several decades. We have treated two cohorts of rGBM patients, one consisting of patients with early progression, and one consisting of patients with progression following several cycles of adjuvant temozomolide chemotherapy, with autologous dendritic cells pulsed with autologous tumour cell lysate (DCVax®-L). Such treatment is intended to activate the immune system against the tumour cells, with the expectation that the ensuing immune attack may delay progression and time to death. To determine survival characteristics of patients with rGBM who are treated with DCVax-L. Disease progression in patients with GBM was determined through magnetic resonance imaging. Progression needed to be determined by independent review on two consecutive scans for early progressor classification to avoid enrolling patients with pseudoprogression. Assessment of progression was done using modified RANO criteria. Nineteen (19) patients diagnosed with GBM were determined to have rapid recurrence following radiation therapy with concomitant temozolomide chemotherapy. The life expectancy for such patients is typically poor, and they were provided the DCVax-L treatment as part of a compassionate use approach in parallel to ongoing late stage clinical trials. Median overall survival in this cohort from initial GBM diagnosis is 15.1 months (95% confidence interval (CI): 10.5–17.2), and the range is 8.1–>31 months. A literature search revealed six publications with comparable populations of patients (Brandes et al., 2008; Roldan et al., 2009; Sanghera et al., 2010; Kang et al., 2010; Gunjur et al., 2011; Linhares et al., 2013). The table below demonstrates that these patients typically have a life expectancy of 8–10 months. Reference (n) Population Median Survival (95% CI) DCVax-L (19) post RT+chemo, confirmed 2 months later 15.1 months (10.5–17.2) Brandes et al. (2008) (18) PD at 4 weeks pos RT+chemo, confirmed after two more tmz cycles 10.2 months (n.a.) Roldan et al. (2009) (10) PD at 4–6 weeks post RT+chemo, confirmed after ⩾ 1 more tmz cycle(s) 9.1 months (4.9–19.1) Kang et al. (2010) (10) PD at two consecutive scans post RT+chemo 10.8 (n.a.) Sanghera et al. (2010) (29) PD at two consecutive scans within 8 weeks post RT+chemo8.3 months (n.a.) Gunjur et al. (2011 (27) PD at two consecutive scans within 3 months post RT+chemo, or clinical deterioration 10.4 months (n.a.) Linhares et al. (2013) (13) PD at two consecutive scans within 3 months post RT+chemo 9.0 months (3.7–14.3) A second cohort of patients with rGBM consisted of eight patients with recurrence following several adjuvant temozolomide treatment cycles. Median overall survival (OS) for these patients is 14.7 months from the time of surgery for first recurrence. The comparator for this cohort is derived from Friedman et al. (2009), who reported mOS of 8.7–9.3 months from the time of first recurrence for rGBM patients treated with Bevacizumab with or without irinotecan. The results obtained in two cohorts of patients with rGBM suggest that treatment with autologous DC pulsed with autologous tumour cell lysate can extend survival by 5 months or more.

Abstract Introduction: Preclinical models have shown that activated DC's can effectively clear both injected (local) and non-injected (distal) inoperable tumor lesions. Based on this strong rationale a Phase I trial was designed to exploit this finding in late stage solid tumors. Methods: We designed a phase I study to determine the safety of intratumoral injection of activated DC by administering the product repeatedly until disease progression or unacceptable toxicity, in advanced cancers. Endpoints included maximum tolerated (MTD), dose limiting toxicities (DLT), safety, and immune response criteria (iRC) and RECIST. The treatment consisted of image-guided intratumoral (IT) injections of autologous, activated dendritic cells (DCVax-Direct,). Injections were given on days 0, 7 and 14, followed by booster immunizations at weeks 4, 8 and 16. Three dose levels, at 2 million, 6 million or 15 million DC per injection, were tested. Concomitant, serial biopsies were performed at the time of the vaccination in the absence of toxicity /progression. Systemic immune responses were tracked through evaluation of T cell subsets and cytokines in circulation, and through T cell receptor (TCR) sequencing in the tumor tissue and in the periphery. Results: To date, 40 patients (men, n = 18; women, n = 22), median age 53.7 (range 30 - 73) years, median of 3.1 (1 - 6) prior therapies (including 1 patient with prior immune therapy) were enrolled. Seventeen patients were treated at the 2 million dose level, 19 at the 6 million dose level, and 3 at 15 million. The MTD has not been reached and there were no dose limiting toxicities. Two patients experienced Grade 3/4 drug related toxicities : one case of fever and dehydration and one case of systemic inflammatory response syndrome. Patterns of immunological reactivity were assessed by pathological scoring on tumor biopsies for 29 patients, and included increasing necrosis in 62% of patients and emergence or amplification of infiltrating T cells in 55%. In-depth study was carried out in a patient with therapy-refractory, de-differentiated liposarcoma whose imaging at 12 weeks post initial injection revealed necrosis in the primary tumor and stable lung metastases. Biopsies demonstrated an intra-tumoral inflammatory response consisting of lymphocytes, macrophages and TIA-1 expressing cells, suggesting cytolytic activity. TCR sequencing revealed the presence of shared TCR sequences in the tumor as well as in circulation, demonstrating a systemic anti-tumor response. Analysis of T cell subsets in circulation demonstrated normalization of the CD4/CD8ratio. Conclusion: Immunotherapy with partially activated DC's injected IT demonstrate early signals of immune reactivity even in late stage patients with cancer. Preliminary data support the generation of anti-tumor effects following IT injection of the partially activated, autologous DC’s. Citation Format: Vivek Subbiah, Ravi Murthy, David S. Hong, Robert E. Brown, Robert Prins, Chitra Hosing, Mary McGuire, Aung Naing, Siquing Fu, Tina Chou, Quan Lin, Richard P. Guevarra, Anthony Conley, Indreshpal Kaur, Funda Meric-Bernstam, Marnix Bosch. Clinical and immunopathological effects following Image-guided intratumoral injection of activated, autologous dendritic cells in patients with advanced solid cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2499. doi:10.1158/1538-7445.AM2015-2499

TPS3133 Background: Dendritic cells (DC) are antigen presenting cells proficient in inducing de novo immune responses, and the presence of intratumoral DCs confers a survival advantage to patients, likely due to an improved balance between the immune system and the growing tumor lesion. We have initiated a Phase I/II clinical trial to exploit this finding, by using partially activated autologous DCs (aDC; DCVax-Direct) for intratumoral injection in inoperable tumors for which limited treatment options exist. These aDC retain antigen uptake and presentation capability and are conditioned to complete the maturation process following injection, resulting in initiation of a broad anti-tumor immune response. Preclinical animal data have demonstrated that these aDC can mobilize both local and systemic immune responses, and effectively clear both injected (local) and non-injected (distal) inoperable tumor lesions. Methods: The Phase I component of the trial aims to enroll 6 patients each in following indications: colorectal cancer, lung cancer, breast cancer with brain metastases, pancreatic cancer, melanoma and ‘other’. Patients must have had at least one recent anti-tumor treatment other than active immune therapy prior to enrollment into the trial. A dose escalation across indications investigates the safety of 3 dose levels. The aDC are injected intratumorally, using imaging guidance, at days 0, 7 and 14, followed by injections at 8 and 16 weeks. Initial DLT assessments are done following the first three injections. Tumor biopsies are taken at the time of injections to assess local effects on the injection of aDC, and tumor response is assessed using both RECIST and Immune Related Response Criteria, starting 8 weeks after the first injection. The first dose cohort of the Phase I component has completed DLT assessments, and the second dose cohort’s enrollment is nearly complete. In addition, the “other” cohort of multiple cancers has been fully enrolled. Correlative immune-biomarkers studies to evaluate response and/or resistance mechanisms are planned. The Phase II component will enroll 24 patients in a selected indication, based on the results obtained in Phase I. Clinical trial information: NCT01882946.

Meeting abstracts Cancer vaccines aiming to induce anti-tumor immune responses are generally considered most effective in an environment with minimal residual disease, due to the immunosuppressive effects exerted by most cancers. We hypothesized that appropriately activated autologous dendritic

Novel strategies for the therapy of recurrent ovarian cancer are warranted. We report a study of a combinatorial approach encompassing dendritic cell (DC)-based autologous whole tumor vaccination and anti-angiogenesis therapy, followed by the adoptive transfer of autologous vaccine-primed CD3/CD28-co-stimulated lymphocytes. Recurrent ovarian cancer patients for whom tumor lysate was available from prior cytoreductive surgery underwent conditioning with intravenous bevacizumab and oral metronomic cyclophosphamide, sequentially followed by (1) bevacizumab plus vaccination with DCs pulsed with autologous tumor cell lysate supernatants, (2) lymphodepletion and (3) transfer of 5 × 109 autologous vaccine-primed T-cells in combination with the vaccine. Feasibility, safety as well as immunological and clinical efficacy were evaluated. Six subjects received this vaccination. Therapy was feasible, well tolerated, and elicited antitumor immune responses in four subjects, who also experienced clinical benefits. Of these, three patients with residual measurable disease received outpatient lymphodepletion and adoptive T-cell transfer, which was well tolerated and resulted in a durable reduction of circulating regulatory T cells and increased CD8+ lymphocyte counts. The vaccine-induced restoration of antitumor immunity was achieved in two subjects, who also demonstrated clinical benefits, including one complete response. Our findings indicate that combinatorial cellular immunotherapy for the treatment of recurrent ovarian cancer is well tolerated and warrants further investigation. Several modifications of this approach can be envisioned to optimize immunological and clinical outcomes.

Meeting abstracts Dendritic cells (DC) are acknowledged to be quintessential in the armamentarium to mount anti-tumor immune responses and have been utilized in varying capacities for cancer immunotherapy. Recent advancements & lessons leant from prior DC therapies have revealed that major barriers