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Adoptive Cell Therapy for B-Cell Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation With Costimulated, Tumor-Derived Lymphocytes

Phase 1
18 Years
75 Years
Not Enrolling
Chronic Lymphocytic Leukemia

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Trial Information

Adoptive Cell Therapy for B-Cell Malignancies After Allogeneic Hematopoietic Stem Cell Transplantation With Costimulated, Tumor-Derived Lymphocytes


- The prognosis for patients with B-cell lymphoid malignancies (BCL) with relapse or
refractory disease after allogeneic hematopoietic stem cell transplantation (AlloHSCT)
is poor. Effective therapy for patients who fail withdrawal of immune suppression and
administration of donor lymphocyte infusions (DLI) has not been identified.

- In the setting of recurrent or refractory BCL, the immunologic graft-versus-tumor (GVT)
effect generated by unmanipulated donor lymphocytes is often not durable and can be
accompanied by graft-versus-host disease (GVHD).

- We have hypothesized that lymphocytes found in tumor after alloHSCT are of donor
origin, and because they are tumor-derived, they may be tumor-specific in their homing
and antigen specificity characteristics. Similarly, inpatients with bone marrow
involvement with tumor, the marrow may be enriched with similarly tumor-specific T
cells. Further, activation and expansion of these cells through CD3/CD28 costimulation
may yield a more effective form of cell therapy than DLI after alloHSCT, with enhanced
GVT effects and less GVHD.


- To evaluate the feasibility of isolating and expanding clinically relevant numbers of
TDL from patients after alloHSCT.

- To determine the safety, vis-a-vis infusion toxicities and/or GVHD, of administering


- Adults with B cell malignancies with tumor that has not responded to successful T cell
engraftment after alloHSCT, withdrawal of immune suppression and administration of
donor lymphocyte infusion will be eligible for this trial.

- Subjects must have a minimum of 1.5 cm of accessible tumor which is amenable to
resection with minimal surgical morbidity and/or bone marrow tumor involvement.


- Subjects will have accessible lesion surgically resected and/or harvested via bone
marrow aspiration.

- Lymphocytes will be liberated and expanded using a co-stimulatory approach with
anti-CD3/CD28 magnetic beads to generate TDL and/or marrow-TDL.

- 1.0 x 10(6) - 1.0 x 10(8) TDL will be administered.

- Subjects will be monitored for the development of infusion reactions (in-hospital for
24 hours after infusion), GVHD (weekly for four weeks then monthly) and tumor responses

- Two cohorts will be enrolled, with an arm evaluating TDL from resected tumor and an arm
to evaluate marrow-TDL from tumor-involved bone marrow. For the TDL arm, 15 to 18
patients and up to 18 donors will be enrolled; for the marrow-TDL arem, 15 patients and
up to 15 donors will be enrolled. Both arms will test the primary endpoints of
feasibility (with at least 11 of 15 tumors yielding 1.0 x 10(6) TDL/kg meeting defined
release criteria) and safety (primarily defined as having a no greater risk of
developing grade II-IV acute GVHD by day 28 as standard therapy with unmanipulated

Inclusion Criteria



1. Patients must have received allogeneic HSCT for B-cell malignancies (BCL),
specifically Hodgkin's and non-Hodgkin's lymphomas, chronic lymphocytic leukemias,
non T-cell acute lymphoblastic leukemia (B-cell ALL), or multiple myeloma, and must
have persistent disease that has failed to respond after a minimum of four weeks to:

2. Donor Engraftment Status: Patients must have had evidence of stable or increasing
donor engraftment over the preceding three months and at least 50% donor chimerism in
the bone marrow, whole blood and/or circulating CD3+ lymphoid pool.

3. A trial of withdrawal of immunosuppressive therapy, including trials that are
discontinued due to development of GVHD

4. Receiving at least one DLI with a minimum T cell dose of 1 x 10(7) CD3+ cells/kg.

- Patients who have persistent cancer after treatment with an alternative donor
alloHSCT (e.g., haploidentical, matched unrelated, umbilical cord blood) or any
patient for whom a donor cell product is unavailable and/or timely donor
collection is not feasible may be included without failing DLI.

- Presence of bone marrow involvement with tumor and/or at least one resectable
lymph node or other tumor focus that is a minimum of 1.5 cm(3) (estimated size
from which at least 1.0 x 106 TNC/kg can be generated):

5. Resectable defined on a case-by-case basis, in collaboration with the Surgical
Consult Service.

6. For surgical tumor resection, the expected procedure must be associated with minimal
morbidity and minimal hospitalization.

7. In addition to a resectable lesion, there must be at least one other site of disease
that permits monitoring for response to therapy.

8. Patients must be 18 - 75 years of age.

9. ECOG performance status less than or equal to 2 (Karnofsky performance status greater
than or equal to 60%).

10. Life expectancy > 3 months.

11. Minimal to no clinical evidence (Grade 0 to 1) of acute GVHD or limited-stage chronic
GVHD while off of systemic immunosuppressive therapy for at least four weeks.
Subjects who require continued prophylaxis with steroid-sparing agents,
e.g.,cyclosporine, or whose disease is controlled with local therapy, e.g., topical
steroids or budesonide, will be eligible for enrollment.

12. Provision for a Durable Power of Attorney.

13. Ability to give informed consent.

1.4 Eligibility of Recipients is not contingent upon enrollment of the donor.


Note: Donor enrollment is not required to meet the primary objectives of this protocol and
will not affect eligibility of recipients.

1. Donor must be the same individual whose cells were used as the source for the
patient's original stem cell transplant

2. Adequate venous access for peripheral apheresis, or consent to use a temporary
central venous catheter for apheresis.

3. Donors must be HIV negative, hepatitis B surface antigen negative, and hepatitis C
antibody negative.



1. Active infection that is not responding to antimicrobial therapy.

2. Active psychiatric disorder which may compromise compliance with transplant protocol,
or which does not allow for appropriate informed consent (as determined by Principal
Investigator and/or his designee).

3. Pregnant or lactating. Patients of childbearing potential must use an effective
method of contraception. The effects of the immunosuppressive medications that could
be required to treat GHVD are likely to be harmful to a fetus. The effects upon
breast milk are also unknown and may be harmful to an infant.

4. Serum total bilirubin > 2.5 mg/dl, serum ALT and AST values greater than or equal to
2.5 times the upper limit of normal. If the abnormal liver function is attributable
to liver involvement by malignancy, patients may be eligible with serum total
bilirubin up to 5.0 mg/dl, and serum ALT and AST values up to 5.0 times the upper
limit of normal, provided the patient has no evidence of impending hepatic failure
(encephalopathy or prothombin time > 2 time the upper limit of normal).

5. Minimum absolute neutrophil count of 500 cells/microl, unless attributable to tumor.

6. Untreated leptomeningeal involvement with malignancy.


1. History of psychiatric disorder which may compromise compliance with transplant
protocol, or which does not allow for appropriate informed consent.

2. History of hypertension that is not controlled by medication, stroke, or severe heart
disease (donors with symptomatic angina will be excluded). Donors with a history of
coronary artery bypass grafting or angioplasty who are symptom free will receive a
cardiology evaluation and be considered on a case-by-case basis.

3. Donors must not be pregnant. Donors of childbearing potential must use an effective
method of contraception.

4. Anemia (Hb < 11 gm/dl) or thrombocytopenia (platelets < 100,000 per microl).
However, potential donors with Hb levels < 11 gm/dl that is due to iron deficiency
will be eligible as long as the donor is initiated on iron replacement therapy. The
NIH Clinical Center, Department of Transfusion Medicine will determine the
appropriateness of individuals as donors.

Type of Study:


Study Design:

Primary Purpose: Treatment

Outcome Measure:

To evaluate the feasibility of administering ex-vivo costimulated/expanded tumor-derived lymphocytes (TDL) in patients with persistent or recurrent B-cell lymphoid malignancies (BCL) following treatment with allogeneic hematopoietic stem cell tr...

Principal Investigator

Elise C Kohn, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute (NCI)


United States: Federal Government

Study ID:




Start Date:

January 2007

Completion Date:

April 2013

Related Keywords:

  • Chronic Lymphocytic Leukemia
  • Adoptive Immunotherapy
  • Tumor Infiltrating Lymphocytes
  • Refractory Tumor
  • Resection
  • B-Cell Malignancies
  • Chronic Lymphocytic Leukemia
  • BCL
  • B-Cell Lymphoid Malignancy
  • Leukemia
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Leukemia, Lymphoid



National Institutes of Health Clinical Center, 9000 Rockville PikeBethesda, Maryland  20892