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To date, despite recent progress in the treatment of Plasma Cell Myeloma (PCM), it remains an incurable disease in which prolonged therapy (maintenance) appears to be beneficial. Th1 immunity is critical in tumor immune surveillance and immune mediated tumor eradication, in particular of PCM. Immune reconstitution deficiency following autologous stem cell transplantation (AHCT) is believed to be a barrier to tumor eradication. Immunotherapy efforts and attempts to boost immunity with adoptive cell transfer have been thwarted by the short life span of the transferred cells. In our pre-clinical work, we found that human Th1/Tc1 lymphocytes, generated ex vivo in the presence of rapamycin (“T1.R”), prolonged engraftment in a human-into-murine model of xenogeneic GVHD. Based on these data, we have implemented a phase I, dose escalation clinical trial to evaluate the feasibility and toxicity of the adoptive transfer of autologous T1.R lymphocytes following AHCT in subjects with recurrent or newly diagnosed high-risk PCM. Subjects are receiving T1.R cells at doses ranging from 1x105 to 45x106 cells /kg. To generate T1.R cells, lymphocytes are collected by steady-state apheresis prior to hematopoietic progenitor cell mobilization/collection; elutriated lymphocytes are then cultured for 6 days using CD3, CD28 co-stimulation, polarizing cytokines (IL-2 + IFN-alpha), and high-dose rapamycin (1 μmol) and administered 6-8 weeks following AHCT. T1.R cells were generated in all cases (n=13); eight subjects have safely received T1.R cells at a median of 55 days post-AHCT. There have been no clinical adverse events attributable to the T1.R cells, and there has been no post-infusion serum elevation of the following cytokines tested at 1h, 4h, 24h, 48h, 72h and 7, 14 and 28 days: GM-CSF, INF-g, IL-1β, IL-6, IL-8 and TNF-α. Current accrual is proceeding at the 5 x 106 cells/kg cohort. T1.R cell recipients have in general shown a disease response (see Table), although the median post-T1.R follow-up is only 137 days. In conclusion, autologous T1.R cells can be generated and appear safe to infuse at evaluated doses after AHCT in patients with PCM.
UPN
| Age
| Sex
| Disease; disease Status pre T1.R
| T1.R dose (x106/kg)
| Disease Status post T1.R
| F/U post T1.R (days) |
2
| 36
| F
| λ chain; refractory; CR
| 0.1
| PD at d180
| 347
|
3
| 58
| F
| λ chain; recurrent; VGPR
| 3.0
| PD at d28
| 187
|
5
| 41
| F
| IgG λ; refractory; SD
| 0.5
| VGPR
| 257
|
6
| 66
| F
| IgG λ; refractory; PR
| 1.0
| Continuing PR
| 221
|
7
| 36
| F
| IgG λ; refractory; VGPR
| 5.0
| Continuing VGPR
| 137
|
8
| 62
| F
| IgG λ, refractory; PR
| 5.0
| Continuing PR
| 39
|
9
| 71
| M
| IgG κ, high-risk; VGPR
| 5.0
| CR
| 102
|
10
| 36
| M
| IgA κ, high-risk; CR
| 3.0
| sCR
| 67
|