Multi-Center Phase I Study of Th1/Tc1 Immunotheraphy Following Autologous Hematopoietic Progenitor Cell Transplantation in High Risk Multiple Myeloma
- Single or tandem Autologous Hematopoietic Cell Transplantation (AHCT) are the standard
of care for newly diagnosed Multiple Myeloma (MM) which, despite recent progress both
with ASCT and the introduction of new drugs, continues to be mostly incurable. While
non-myeloablative allogeneic transplant is being investigated with encouraging results,
subjects who are not candidates are left without satisfactory therapeutic alternatives.
- A new investigational approach to MM treatment consists of adoptive autologous
immunotherapy. Both pre-clinical and preliminary clinical data suggest that this
approach can mediate both immune reconstitution and anti-tumor effects following AHCT.
Potentially, it may be possible to harness such T cell-mediated effects without the
need for myeloablative high-dose chemotherapy and AHCT.
- We will evaluate this new form of therapy using an anti-CD3, anti-CD28 co-stimulated
autologous T cells ex vivo expansion in a short term (6 days) culture with high-dose
rapamycin, a system found in murine models to generate Th1 / Tc1 polarized T cells
(Th1.rapa cells) that are both rapamycin-resistant and apoptosis-resistant with a
greatly increased in vivo survival.
- As Th1 /Tc1 polarized lymphocytes are pivotal in immune mediated tumor surveillance or
eradication and based on our and others' pre-clinical data, we hypothesize that
adoptive transfer of Th1.rapa cells to moderately immune depleted subjects
(post-transplant subjects) will yield Th1 cytokine polarity and thereby will represent
a T cell population of potential therapeutic benefit for patients with MM. [NOTE: we
are assessing cytokine polarity but not able to assess in vivo persistence].
-Evaluate the feasibility and toxicity of an infusion of autologous, ex vivo
rapamycin-generated, anti-CD3 and anti-CD28 co-stimulated, Th1/Tc1 lymphocytes (Th1.rapa
cells) in subjects newly diagnosed with high-risk multiple myeloma who are 6 weeks post-
- Characterize the cellular aspects and cytokine phenotype of immune reconstitution in
recipients of Th1.rapa cells.
- Characterize potential clinical anti-tumor responses in a preliminary manner through
determination of disease-free survival, relapse-free and overall survival
- Characterize the safety and potential anti-tumor effects of the Th1.rapa cell
population in the
context of immune-depleting chemotherapy consisting of either a 7-day or 14-day course of
pentostatin combined with low-dose cyclophosphamide.
-Adults newly diagnosed with or receiving induction therapy for MM with established adverse
- Subjects must have first received induction therapy or salvage therapy followed by 1 or
2 ASCT as indicated clinically.
- Phase I dose escalation study of the administration of Th1.rapa cells.
- Th1.rapa cells infusion at approximately 6 weeks following the last ASCT.
Seven Th1.rapa cell doses will be tested in cohorts of 1-6 subjects each: ranging from 10(5)
to 45 x 10(6) cells/Kg of body weight.
In a subset of patients, Th1.rapa cell infusion will be evaluated after administration of a
7-day or 14-day course of immune-depleting chemotherapy (pentostatin plus cyclophosphamide
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Evaluate the feasibility and toxicity of an infusion of autologous, ex vivo rapamycin-generated, anti-CD3 and anti-CD28 co-stimulated, Th1/Tc1 lymphocytes (Th1.rapa cells) in subjects newly diagnosed with high-risk multiple myeloma.
Claude Sportes, M.D.
National Cancer Institute (NCI)
United States: Federal Government
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Bethesda, Maryland 20892|
|Hackensack University Medical Center||Hackensack, New Jersey 07601|