Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor Adoptive T Cell Therapy During Recover From Myeloablative Chemotherapy and Hematopoietic Stem Cell Transplantation
Background: Malignant brain tumors now represent the most frequent cause of cancer death in
children1. Despite aggressive and highly toxic multi-modality therapy including surgery,
craniospinal radiation, and high-dose chemotherapy coupled with peripheral blood stem cell
transplantation (HDC + PBSCT), almost half the children diagnosed with the most common
malignant brain tumors, medulloblastoma and primitive neuroectodermal tumors (MB/PNETs),
will still die from recurrent disease. Furthermore, survivors are often left with severe
and lifelong treatment-associated cognitive and motor deficits. The development of more
effective and tumor-specific therapies that will not add further toxicity to existing
treatments is paramount in improving clinical outcomes for children affected by MB/PNETs.
Immunotherapy targeting tumor-specific antigens expressed within brain tumors is a modality
potentially capable of meeting this clear and urgent need8.
Despite considerable advancements and promising clinical results observed in immunotherapy
trials at our center and others directed against adult malignant brain tumors, efforts in
the immunologic treatment of pediatric brain tumors have been limited to relatively few
notable studies. This is due, at least in part, to the often limited viable tumor tissue
available for tumor cell-based vaccine preparations, and the lack of identification of
consistently expressed tumor-specific antigens within these cancers.
The use of total tumor RNA (TTRNA)-loaded dendritic cells (DCs) was pioneered by Drs. Nair
and Gilboa at our institution, as a novel platform for inducing potent immunologic responses
against the variety of uncharacterized and patient-specific antigens present within
malignant tumor cells. The investigators have demonstrated that sufficient RNA for clinical
vaccine preparations can be amplified with high fidelity using existing molecular
technologies from as few as 500 isolated pediatric and adult brain tumor cells, thus
allowing vaccine preparation from surgical biopsies and even microdissected archival tumor
specimens. The investigators are currently exploring adoptive cellular therapy using
amplified tumor RNA-pulsed DCs and autologous lymphocyte transfer (DC + ALT therapy) in
adult patients with recurrent GBM (glioblastoma) (FDA Biological-Based Investigational New
Drug (BB-IND)-13630; Duke Institutional Review Board (IRB) protocol 6677; PI: Duane A.
Mitchell, M.D., Ph.D.). In this proposal, the investigators aim to extend evaluation of this
novel platform to the treatment of recurrent MB/PNETs (reMB/PNETs) during hematopoietic
recovery from HDC + PBSCT.
Immunotherapy administered during recovery from HDC (Group A) or non-myeloablative (NMA)
salvage chemotherapy (Group B) may have tremendous advantages, as adoptive cellular therapy
following lymphodepletive condition regimens has emerged as the most effective treatment
strategy for advanced and refractory melanoma, with remarkable objective clinical responses
in up to 75% of treated patients, including durable complete regressions of metastatic
lesions within the central nervous system (CNS). Though the mechanisms by which
lymphodepletion enhances immunotherapy in humans are not well elucidated, elegant studies in
murine tumor models have highlighted the depletion of immunosuppressive regulatory T cells
(Tregs), increased bioavailability of inflammatory cytokines and homeostatic proliferative
cytokines (most notably interleukin (IL)-7 and IL-15) after removal of host lymphocytes and
natural killer (NK) cells that compete with transferred tumor-specific T cells, and
increased toll-receptor agonistic signals due to systemic release of gut microbial antigens
during myeloablative therapy as the key catalysts for induction of potent anti-tumor
Objective/Hypothesis: Our hypothesis is that DC + ex vivo expanded Autologous Lymphocyte
Transfer(xALT) therapy targeting reMB/PNETs during recovery from myeloablative chemotherapy
will be safe and will prolong the 12-month progression-free survival (PFS-12) (H0: 3.14(pi)
≤ 0.33; H1: 3.14(pi) > 0.55) in children and young adults with reMB/PNETs.
Specific Aims: A Phase I/II clinical trial of DC + ALT therapy during hematopoietic
recovery from HDC + PBSCT in pediatric patients with reMB/PNETs will be conducted with the
1. Establish the safety of DC + ALT therapy during hematopoietic recovery from HDC + PBSCT
(Group A) or NMA salvage chemotherapy (Group B) in children with reMB/PNETs;
2. Determine the impact of DC + ALT therapy on progression-free survival (PFS) and overall
survival (OS) of children with reMB/PNETs compared to historical controls;
3. Investigate the correlation between clinical outcome and the frequency and persistence
of tumor-specific T cells in the peripheral blood of treated patients;
4. Determine the impact of induction therapy and HDC + PBSCT (Group A) or NMA salvage
chemotherapy (Group B) on circulating levels of homeostatic and inflammatory cytokines,
toll-receptor activation status, and on the functional recovery of lymphocyte and NK
cellular subsets in children with re-MB/PNETs receiving DC + ALT therapy; Study Design:
A single-arm, prospective Phase I/II clinical trial of DC + xALT therapy is planned in
pediatric and young adult patients with reMB/PNETs. The maximum tolerated dose of
adoptively transferred tumor-specific lymphocytes will be established during Phase I
using a 3+3 study design and then 35 patients will be treated during Phase II with the
maximum tolerated dose(MTD) of DC + xALT therapy to estimate the clinical efficacy. The
primary endpoint of the Phase I trial will be safety and defining the MTD. The primary
endpoint of the Phase II trial will be PFS-12. With 35 patients, the Phase II study
will have 90% power to differentiate between PFS-12 of 33% (null hypothesis) and 55%
(alternative hypothesis) assuming a type I error rate of 0.10.
Impact: These studies will address the clear and urgent need for novel and less toxic
therapy for the treatment of MB and PNETs in the pediatric population. As the leading cause
of cancer related deaths in children, this therapy has significant potential to favorably
alter the disease outcome for pediatric cancers overall.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Establishing the safety of DC + xALT therapy in this patient population with total tumor RNA (TTRNA)-xALT and TTRNA-DCs will be the primary goal in the Phase I portion of the trial.
Number of participants with adverse events as a measure of safety and tolerability.
Duane A Mitchell, M.D., Ph.D.
United States: Food and Drug Administration
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