B-cell Acute Lymphoblastic Leukemia Clinical Trial
Official title:
Pilot Study of Redirected Haploidentical Natural Killer Cell Infusions for B-Lineage Acute Lymphoblastic Leukemia
Modern therapy for patients with B-lineage acute lymphoblastic leukemia (ALL) is based on
intensive administration of multiple drugs. In patients with relapsed disease, treatment
response is generally poor; for most patients, particularly those who relapse while still
receiving frontline therapy, the only therapeutic option is hematopoietic stem cell
transplantation (HSCT). There is no proven curative therapy for patients who relapse after
transplant.
Natural killer (NK) cells have powerful anti-leukemia activity. In patients undergoing
allogeneic HSCT, several studies have demonstrated NK-mediated anti-leukemic activity. NK
cell infusions in patients with leukemia have been shown to be well tolerated and void of
graft-versus-host disease (GVHD) effects.
NK cell cytotoxicity is most powerful against acute myeloid leukemia (AML) cells, whereas
their capacity to lyse ALL cells is generally low. We have developed a novel method to expand
and redirect NK cells towards CD19, a molecule highly expressed on the surface of B-lineage
ALL cells but not expressed on normal cells other than B-lymphocytes. In this method, donor
NK cells are first expanded by co-culture with the cell line K562-mb15-41BBL and interleukin
(IL)-2. Then, the expanded NK cells are transduced with a signaling receptor that binds to
CD19 (anti-CD19-BB-zeta). NK cells expressing these receptors showed powerful anti-leukemic
activity against CD19+ ALL cells in vitro and in an animal model of leukemia.
This study will assess the feasibility, safety and efficacy of infusing expanded, activated
redirected NK cells into research participants with B-lineage ALL who have persistent disease
after intensive chemotherapy . In this same cohort, we will study the in vivo lifespan and
phenotype of these redirected NK cells.
1.0. Rationale
In contrast to the well-established cytotoxicity of NK cells against AML cells, their
capacity to lyse ALL cells is generally low and difficult to predict. We sought to overcome
this intrinsic resistance by transducing CD56+ CD3─ NK cells with chimeric receptors directed
against CD19, a molecule widely expressed by malignant B cells. Expression of anti-CD19
receptors linked to CD3zeta overcame NK resistance and markedly enhanced NK cell-mediated
killing of leukemic cells. This result was significantly improved by adding the 4-1BB
costimulatory molecule to the chimeric anti-CD19-CD3zeta receptor: the cytotoxicity produced
by NK cells expressing this construct uniformly exceeded that of NK cells whose signaling
receptors lacked 4-1BB, even when natural cytotoxicity was apparent (Imai et al., Blood
2005). NK cells expressing anti-CD19 receptors also exerted vigorous anti-ALL activity in a
murine model of leukemia (Shimasaki et al., Cytotherapy 2012). Our findings indicate that
enforced expression of signaling receptors by NK cells might circumvent inhibitory signals,
providing a novel means to enhance the effectiveness of anti-ALL NK cell therapy.
The great anti-leukemic efficacy of genetically modified NK cells shown in our preclinical
studies, together with the demonstrated feasibility of infusing durable haploidentical NK
cells in a non-HSCT setting and the established expertise by the NUH team in cell therapy
(the only center in Asia accredited by Foundation for the Accreditation of Cellular Therapy,
FACT), form a compelling rationale for the clinical testing of these NK cells.
The preparation of the key reagent (anti-CD19-BB-zeta mRNA) is finalized in the Tissue
Engineering & Cell Therapy (TECT) Laboratory at NUH, where the GMP-compliant MaxCyte
electroporator is located. The feasibility of large-scale expansion of NK cells has been
demonstrated (Shimasaki et al. Cytotherapy 2012), and the feasibility of large-scale
electroporation validated in the TECT laboratory.
We will use flow cytometric and MRD technologies, to determine the presence of persistent
disease , and will include in this study only patients with a limited amount of residual
disease (<1% leukemic lymphoblasts among normal bone marrow cells). We will use the same MRD
methods to monitor the effects of treatment infusions. We do not expect that the conditioning
regimen will have much effect by itself on leukemic cell counts, as the patients eligible for
the study will have disease that is resistant to many anti-leukemic drugs. Nevertheless,
because the conditioning regimen itself may have some salutary effects, it will be important
to screen the peripheral blood and/or bone marrow for the presence of leukemic blast cells
through all stages of the procedure, i.e., before, during, and after conditioning and after
the NK cell infusion. The presence of leukemic cells in will be closely monitored by flow
cytometry or PCR amplification of antigen-receptor genes (sensitivity for either method: 1
leukemic cell in 10,000) to shed some light on the relative effect of each intervention.
2.0. Hypothesis and Objectives
The main hypothesis to be tested in this study is that infusion of NK cells expressing
anti-CD19-BB-zeta receptors by electroporation can produce measurable clinical responses in
patients with resistant B-lineage ALL.
3.0. Primary Objectives
- To determine the feasibility and safety of redirecting NK cells with an anti-CD19
chimeric antigen receptor by mRNA electroporation in a clinical setting.
- To determine the efficacy of anti-CD19 redirected NK cells in research participants with
B-lineage ALL who have persistent disease as determined by MRD methods after intensive
chemotherapy.
4.0. Secondary Objectives
- To study the persistence and phenotype of redirected NK cells in research participants
with B-lineage ALL who have residual disease after intensive chemotherapy.
5.0. Endpoints
In this study, treatment response will be measured by comparing MRD levels before and at
several intervals after NK cell infusion.Achievement of MRD negativity in bone marrow, i.e.,
< 0.01% blasts by flow cytometry or PCR, will be regarded as a complete response. Partial
response will be defined as ≥ 1 log decrease in MRD levels, while < 1 log decrease in MRD
levels will be regarded as a no response.
Based on previous studies, donor NK cells will be eliminated in most cases by the resurgent
cellular immunity of the haploidentical recipient after the effects of the transient
immunosuppression caused by the conditioning regimen have ceased (typically within 1 month of
infusion). Conceivably, however, NK cell engraftment may persist for a longer period with the
possible risk of prolonged pancytopenia owing to NK cell killing on normal hematopoietic
cells. Because of this possibility, we will plan for HSCT rescue in patients receiving
redirected NK cell infusions. Indeed, for most of the patients eligible for this study, HSCT
would be the treatment intervention regardless of whether they receive NK cell infusions or
not. Because of these considerations, the potential benefits of NK cell therapy should
outweigh its risks for those patients eligible for this study, i.e., patients with persistent
leukemia for whom no other proven effective treatment is available.
Because CD19 is universally expressed on B cells including early B cell precursors, normal
recipient B cell will also be a target for the donor NK cells transduced with the anti-CD19
chimeric receptors. Therefore, transient B-cell lymphopenia and hypogammaglobinemia are
expected. We will monitor the CD19+ blood cell count and measure the Ig levels once a month
and will give the participants intravenous immunoglobulins (IVIG) if their IgG level is lower
than age-specific ranges.
6.0. Summary of Study Design
Peripheral blood cell will be collected by apheresis from donors. After ex vivo expansion for
10 days by coculture with irradiated K562-mb15-41BBL cells (Fujisaki et al, Cancer Res 2009;
Lapteva et al. Cytotherapy 2012) and T-cell depletion, haploidentical NK cells will be
electroporated with anti-CD19-BB-zeta mRNA. Before infusion, patients will receive
immunosuppressive therapy to promote temporary engraftment of NK cells. After infusion, they
will receive IL-2 to support NK cell viability and expansion in vivo. The effects of NK cell
infusion will be determine by comparing MRD levels before and after treatment.
Receptor expression after electroporation is transient and typically declines after 48 hours
becoming undetectable after 96 hours. Because the aim of NK cell therapy is not to induce
durable immunity but to rapidly reduce tumor cell burden, and the infused NK cells are
rejected by the host immune system after approximately 2 weeks of infusion, the transient
nature of the expression should not significantly affect anti-tumor potential. Moreover, by
using this strategy, safety concerns regarding insertional mutagenesis and long-term
persistence of transduced residual T cells do not apply. In any case, we will minimize the
number of residual T cells in the final product as much as possible by depleting the expanded
product of T cells by using the CliniMACS device, and by limiting the number of T cells in
the graft to <0.05 x 10^6/kg.
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