ALBERT

Description: Randomized trials have demonstrated superior progression free (PFS)and overall survival (OS) with autologous stem cell transplant (ASCT) for patients with relapsed chemosensitive non-Hodgkin lymphoma (NHL) compared with conventional dose salvage chemotherapy. More recent trials have proven that ASCT is also feasible in pts with AIDS associated NHL (ARL). However, the impact of the HIV infection on long term outcome is unknown. We therefore, undertook a retrospective case control analysis of ASCT for high risk B cell NHL in HIV positive (HIV Pos) and HIV negative (HIV Neg) pts. Twenty-nine pts with ARL who underwent ASCT between 1998 and 2007 were matched with HIV Neg controls. Pts were matched for gender, time from NHL dx to ASCT, age at ASCT, dz status at ASCT, number of prior regimens, conditioning regimen (chemo vs. FTBI). Histology was matched as closely as possible with the exception that there were more high-grade NHL pts in the HIV Pos group. Patient HIV Pos HIV Neg P value* (* P value by Fishers exact test or Wilson signed rank sum test) Age at ASCT 42 (11–68) 48(21–65) .06 HISTOLOGY Large cell 19 25 Burkitts 10 0 Follicular gr 3 0 3 Marginal zone 0 1 Disease status 1CR/PR 16 16 IF 2 2 1.0 Relapse 11 11 Prior regimens 2(1–4) 2(1–4) .33 Conditioning - - FTBI 4 4 1.0 Non TBI 25 25 Median followup for HIV Pos pts is 46.7 months and 43.3 months for HIV neg controls (NS). Pts engrafted WBC at a median of 10 days (HIV Pos) and 11 days (HIV Neg) (NS) respectively. Non-relapse mortality (NRM) was 8% (95% CI 2–26) in HIV Pos pts and 4% (95%CI 0.7–25)in HIV Neg controls (NS). Two year PFS for the HIV Pos cohort was 76% (95% CI 62–85) and 56% (95% CI 45–66) for the controls (NS). OS was also similar at 75% (95% CI 61–85) versus 75% (95% CI 60–85)respectively{ see figure }. In conclusion, despite the inclusion of more poor risk pts by histology in the HIV Pos cohort, our series demonstrated matching OS for HIV Pos and HIV Neg pts undergoing ASCT for NHL The equivalent NRM also provides further evidence that HIV status does not affect the outcome of ASCT for NHL and therefore, should be considered a standard approach for select pts with ARL. Figure Figure

Description: Background: Autologous stem cell transplantation (ASCT) has become an accepted treatment option for high risk or relapsed ARL. Treatment related mortality is similar to the HIV negative setting. However, ultimately further improvement in ASCT will depend on both effective anti lymphoma therapy and better control of the HIV infection. Highly active antiretroviral therapy (HAART) can lower HIV viral loads to undetectable levels in the peripheral blood, but reservoirs of HIV are still present in the tissues and acquired resistance to HAART also remains a problem. A treatment strategy that would confer intrinsic resistance to HIV could circumvent theses issues. Herein we report on one such strategy using multiplexed RNA based anti-HIV gene transfer strategies to render autologous peripheral blood progenitor cells resistant to HIV. Patients with high risk ARL deemed candidates for ASCT were eligible. Seven subjects with NHL have been enrolled. (4PR, 2 REL, 1CR2), of whom 2 failed screening phase, 1 failed product release test, 2 are pending transplant, and 2 patients have undergone successful transplantation. Median age was 43 yrs at enrollment. Four pts to date were mobilized with chemotherapy plus GCSF and cells were collected for the clinical product (Fx1) and for CD34-selection (CliniMACSª, Miltenyi) and research treatment (Fx2). (see table ) UPN # Fx1 (CD34+/kg) Fx2 (CD34+/kg) Post Selection and transductionCD34+/kg 301 2.8X106 3.5X106 .26 X106 not infused 304 3.9X106 3.6X106 1.2 X106 305 3.4X106 3.8X106 1.4X106 306 5.6X106 8.8X106 pending Three days prior to the completion of CBV (cyclophosphamide 100mg/kg, BCNU 450mg/ m2, VP16 60mg/kg) conditioning, the Fx2 cells were thawed and transduced with a lentivirus vector (LV,rHIV7-ShI-TAR-CCR5Z) encoding 3 RNA elements including short hairpin RNA (shRNA) targeted to HIV tat/rev, a nucleolar localizing TAR decoy sequence, and a ribozyme targeted to CCR5. Cell viability post transduction ranged between 52–64% in three pts. On day 0 Fx2 is given and Fx1 is given 24hrs later (day+1). UPN301 did not receive the transduced Fx2 cells due to a low cell dose. For UPN304 and 305 who received the gene modified Fx2 cells, WBC engraftment occurred at day +11, platelet engraftment at day+16, and there have been no serious adverse events. Results to date at 30 and 60 days post ASCT reveal peripheral blood marking consistent with the ratio of gene modified to unmodified cells infused. Q-PCR analysis demonstrated distribution of genetically modified cells in myeloid and lymphoid lineages, and RT-PCR evidence of shRNA in progeny cells provided further evidence of successful transduction and engraftment of progenitor cells. Follow-up data for these and subsequent patients will be presented at the meeting. Conclusion: Lentiviral vector transduction of autologous peripheral blood progenitor cells with multiplexed RNA is feasible, well tolerated, and led to successful engraftment following high dose chemotherapy for ARL.