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.
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.
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 (
= 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (
< 0.01).
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.
.
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.
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.
The immunotherapy of cancer is predicated on the belief that it is possible to generate a clinically meaningful antitumor response that provides patient benefit, such as improvement in the time to ...progression or survival. Indeed, immunotherapeutics with dendritic cells (DC) as antigen-presenting delivery vehicles for cell-based vaccines have already improved patient outcome against a wide range of tumor types (1-9). This approach stimulates the patient's own antitumor immunity through the induction or enhancement of T-cell immunity. It is generally believed that the activity of cytotoxic T lymphocytes (CTL), the cells directly responsible for killing the tumor cells in vivo, are directed by DC. Therefore, the goal of many current designs for DC-based vaccines is to induce strong tumor-specific CTL responses in patients with cancer. In practice, most studies for DC-based cancer vaccine development have focused on the development of methods that can effectively deliver exogenous tumor antigens to DC for cross-priming of CD8+ T cells through the endogenous MHC class I processing and presentation pathway (10). To date, many methods have been developed or evaluated for the delivery of defined and undefined tumor antigens to DC. This review provides a brief summary on these methods, the techniques used in these methods, as well as the advantages and disadvantages of each method.
Dendritic cells (DC) are increasingly prepared in vitro for use in immunotherapy trials. Mature DC express high levels of surface molecules needed for T cell activation and are superior at ...antigen-presentation than immature DC. Bacillus Calmette-Guerin (BCG) is one of several products known to induce DC maturation, and interferon (IFN)-gamma has been shown to enhance the activity of DC stimulated with certain maturation factors. In this study, we investigated the use of IFN-gamma in combination with the powerful maturation agent, BCG. The treatment of immature DC with IFN-gamma plus BCG led to the upregulation of CD54, CD80, and CD86 in comparison with BCG treatment alone. In MLR or recall immune responses, the addition of IFN-gamma at the time of BCG-treatment did not increase the number of antigen-specific T cells but enhanced the development of IFN-gamma-producing Th1 cells. In primary immune responses, on the other hand, BCG and IFN-gamma co-treated DC stimulated higher proportions of specific T cells as well as IFN-gamma secretion by these T cells. Thus the use of IFN-gamma during BCG-induced DC maturation differentially affects the nature of recall versus naïve antigen-specific T-cell responses. IFN-gamma co-treatment with BCG was found to induce IL-12 and, in some instances, inhibit IL-10 secretion by DC. These findings greatly enhance the potential of BCG-matured dendritic cells for use in cancer immunotherapy.
While there has been significant progress in advancing novel immune therapies to the bedside, much more needs to be done to fully tap into the potential of the immune system. It has become ...increasingly clear that besides practical and operational challenges, the heterogeneity of cancer and the limited efficacy profile of current immunotherapy platforms are the two main hurdles. Nevertheless, the promising clinical data of several approaches point to a roadmap that carries the promise to significantly advance cancer immunotherapy. A new annual series sponsored by Arrowhead Publishers and Conferences aims at bringing together scientific and business leadership from academia and industry, to identify, share and discuss most current priorities in research and translation of novel immune interventions. This Editorial provides highlights of the first event held earlier this year and outlines the focus of the second meeting to be held in 2013 that will be dedicated to stem cells and immunotherapy.
Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.
To investigate whether adding autologous tumor lysate-loaded ...dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.
This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.
The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.
The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.
A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.
ClinicalTrials.gov Identifier: NCT00045968.
PDF
