To investigate feasibility, safety and toxicity as well as immune-response of an allogeneic tumor cell lysate (PheraLys) loaded onto autologous dendritic cells (MesoPher) in resected pancreatic cancer patients who received adjuvant standard of care…
ID
Source
Brief title
Condition
- Exocrine pancreas conditions
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of this project proposal is to determine the feasibility
of administering MesoPher after standard of care adjuvant therapy in patients
with resected pancreatic cancer. We deem this treatment feasible in case 6 out
of 10 patients are able to complete the proposed treatment.
Secondary outcome
As a secondary endpoint we will assess the safety of MesoPher in surgically
resected pancreatic cancer patients.
In addition, we will determine the systemic immune profile, with emphasis on T
lymphocytes, in surgically resected pancreatic cancer patients; and investigate
how these immune profiles are affected by MesoPher treatment for individual
patients.
Background summary
The annual incidence of patients developing pancreatic cancer in the
Netherlands is approximately 3500. In 2030, pancreatic cancer is expected to be
the second leading cause of cancer-related death. The 1-year overall survival
(OS) for pancreatic cancer in the Netherlands is 20%; 5-year OS is only 3%.
Current treatments for pancreatic cancer include cytoreductive surgery, radio-
and chemotherapy. To date, surgical resection is the mainstay of potentially
curative treatment for patients with (borderline) resectable disease. However,
ten years after resection, OS is 4%, demonstrating that cure is exceedingly
rare. Apparently, the vast majority of patients with (borderline) resectable
pancreatic cancer on imaging have occult metastatic disease. In the
Netherlands, almost a third of these patients is found to have more advanced
disease (locally advanced or metastatic) during surgical exploration and
consequently does not undergo a resection. In the end, only 5-25% of all
pancreatic cancer patients are eligible to undergo surgical resection.
We are in need of new treatments in order to curb the progression of pancreatic
cancer. In contrast to radiotherapy and chemotherapy, dendritic cell
vaccination may elicit specific anti-cancer responses without damaging
surrounding healthy tissue and therefore would be a suitable complementary
treatment to the current treatment regime.
While no clinical data is available concerning the efficacy and safety of
allogenic tumor lysate pulsed DC vaccination in patients with pancreatic
cancer, DC therapy with either autologous or allogenic tumor lysate has shown
its feasibility and safety in patients suffering from MM. Here we propose to
use PheraLys, a tumor lysate derived from five different malignant MM cell
lines to load autologous DCs (MesoPher) for patient treatment. Microarray
analysis of these five MM cell lines revealed that PheraLys contains a broad
spectrum (>120) of tumor associated antigens (TAA) and cancer germline antigens
(CGA) which are expected to induce high-avidity T cell responses within the
patients. We argue that MesoPher possesses the potential to induce strong
anti-tumor responses in patients suffering from pancreatic cancer as well,
given the broad overlap of TAA and CGA expression between the two tumor types.
Compared to other cancer types, pancreatic cancer tissue specimens contain a
relatively low number of cancer cells, making autologous tumor lysate for DC
vaccination ineffective. We propose that the use of a lysate derived from five
different MM cell lines to pulse DCs in pancreatic cancer patients has a higher
feasibility than using autologous tumor lysate. Both MM and pancreatic cancer
share multiple, clinically proven TAAs such as but not limited to: WT-1,
mesothelin and MUC-1. In addition, unlike ACT with TCR transduced T cells which
requires patients to have an HLA matching the therapeutic, whole tumor lysate
therapy in the context of DC vaccination is applicable to all patients
regardless of their HLA type.
Therefore, in this study we will primarily investigate whether it is feasible
to use an allogeneic source of tumor antigens from MM cell lines in pancreatic
cancer patients. Our secondary objective is to assess the safety and toxicity
of the treatment as well as the occurrence of anti-tumor/immune responses
within individual pancreatic cancer patients.
Study objective
To investigate feasibility, safety and toxicity as well as immune-response of
an allogeneic tumor cell lysate (PheraLys) loaded onto autologous dendritic
cells (MesoPher) in resected pancreatic cancer patients who received adjuvant
standard of care treatment.
Study design
Single center prospective open label phase I study.
Intervention
Leukapheresis is performed of which the monocytes are used for differentiation
to dendritic cells using specific cytokines. Pulsed autologous dendritic cells
(MesoPher) are re-injected three times every two weeks. After the third
injection with MesoPher, revaccinations to boost the immune system are given
after 3 and 6 months.
Furthermore 3 CT scans will be performed to assess treatment response and
bloodsamples will be collected to monitor the immune system before, during and
after treatment.
Study burden and risks
Patients have to undergo extra outpatient clinic visits for this study and
extra invasive procedures specifically for this trial, i.e. intravenous
catheter placement. Although these are invasive procedures, associated risks
are limited. Intravenous access is necessary during every visit, i.e. for
leukapheresis, for drawing blood samples and for injection of the dendritic
cells. Leukapheresis is a standard procedure and will be performed according to
our internal guidelines. There is a limited risk for transient thrombocytopenia
and leukopenia after performance of the leukapheresis. Adverse events due to
administration of autologous cells that have been loaded with allogeneic human
materials pose a theoretical risk. However, since patients are not treated with
the allogenic lysate itself, but with autologous dendritic cells that have been
processed and therefore only present the lysate-derived antigens, we expect the
associated risks to be limited. Previous clinical studies have shown that
injection with tumor lysate-pulsed autologous dendritic cells was well
tolerated without major systemic toxicity, with the exception of low-grade
flu-like symptoms like fever and rigors.
's-Gravendijkwal 230
Rotterdam 3015 CE
NL
's-Gravendijkwal 230
Rotterdam 3015 CE
NL
Listed location countries
Age
Inclusion criteria
* Surgically resected pancreatic cancer.
* Completed post-operative standard treatment. Patients who did not complete standard of care due to toxicity or who are not able to start standard of care due to specific reasons are allowed to participate in the study after approval of the coordinating investigator.
* No disease activity as assessed by radiological imaging.
* Patients must be at least 18 years old and must be able to give written informed consent.
* Patients must be ambulatory (WHO-ECOG performance status 0,1 or 2) and in stable medical condition.
* Patients must have normal organ function and adequate bone marrow reserve: absolute neutrophil count > 1.0 x 10E9/l, platelet count > 100 x 10E9/l, and Hb > 6.0 mmol/l (as determined during screening).
* Positive DTH skin test (induration > 2mm after 48 hrs) against at least one positive control antigen tetanus toxoid (see section 8.3 for DTH skin test procedure).
* Ability to return to the hospital for adequate follow-up as required by this protocol.
* Written informed consent according to ICH-GCP.
Exclusion criteria
* Medical or psychological impediment to probable compliance with the protocol.
* Current or previous treatment with immunotherapeutic agents.
* Current use of steroids (or other immunosuppressive agents). Patients must have had 6 weeks of discontinuation and must stop any such treatment during the time of the study. Prophylactic usage of dexamethasone during chemotherapy is excluded from this 6 weeks interval.
* Prior malignancy except adequately treated basal cell or squamous cell skin cancer, superficial or in-situ cancer of the bladder or other cancer for which the patient has been disease-free for five years.
* Serious concomitant disease, or active infections.
* History of autoimmune disease or organ allografts (or with active acute or chronic infection, including HIV and viral hepatitis).
* Serious intercurrent chronic or acute illness such as pulmonary disease (asthma or COPD), cardiac disease (NYHA class III or IV), hepatic disease or other illness considered by the study coordinator to constitute an unwarranted high risk for investigational DC treatment.
* Known allergy to shell fish (may contain keyhole limpet hemocyanin (KLH).
* Pregnant or lactating women.
* Inadequate peripheral vein access to perform leukapheresis.
* Concomitant participation in another clinical trial (except participation in a biobank study).
* An organic brain syndrome or other significant psychiatric abnormality which would compromise the ability to give informed consent, and preclude participation in the full protocol and follow-up.
* Absence of assurance of compliance with the protocol. Lack of availability for follow-up assessment.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003485-26-NL |
| CCMO | NL63102.000.17 |