AIDS patients undergoing autologous transplantation for lymphoma were treated with gene-modified peripheral blood derived (CD34+) hematopoietic progenitor cells (HPC) expressing 3 RNA-based anti-HIV moieties (Tat/Rev shRNA, TAR decoy and CCR5 ribozyme). In vitro analysis of gene-modified HPC showed no differences in the hematopoietic potential compared with non-transduced cells. In vitro estimates of gene marking were as high as 22% but declined to ~1% over 4 weeks of culture. Ethical study design required that patients were transplanted with both gene modified and unmanipulated hematopoietic progenitor cell apheresis products (HPC-A). All 4 infused patients engrafted (ANC>500) by day 11 post-infusion and showed no unexpected infusion related toxicities. Persistent vector marking in multiple cell lineages has been observed at low levels for up to 24 months as has expression of siRNA and ribozyme. This is the first demonstration of siRNA expression in human blood cells following transplantation of autologous gene-modified CD34+ HPC. These results support the development of an RNA-based cell therapy platform for HIV. Summary Stem cell gene therapy for HIV results in sustained RNA expression in the blood of patients for up to 2 years following transplant.

The treatment of HIV-associated lymphoma has changed since the widespread use of highly active antiretroviral therapy. HIV-infected individuals can tolerate more intensive chemotherapy, as they have better hematologic reserves and fewer infections. This has led to higher response rates in patients with HIV-associated Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) treated with chemotherapy in conjunction with antiretroviral therapy. However, for patients with refractory or relapsed disease, salvage chemotherapy still offers little chance of long-term survival. In the non-HIV setting, patients with relapsed Hodgkin disease (HD) or non-Hodgkin lymphoma (NHL) have a better chance of long-term remission with high-dose chemotherapy with autologous stem cell rescue (ASCT) compared with conventional salvage chemotherapy. IntroductionThe incidence of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) in HIV-infected individuals is much greater than in the HIV-negative population. 1,2 In earlier decades the treatment of lymphoma in the setting of immune deficiency was far less successful than in the HIV-negative patient. 3 This was in part due to the poor hematologic reserves of HIV-infected patients but was also due to higher rates of infection and higher rates of relapse of the lymphoma. The advent of highly active antiretroviral therapy (HAART) altered the natural history of HIV infection by reducing the incidence of opportunistic infections and improving the underlying immune deficiency. 4 In addition, combining HAART with chemotherapy or consolidating chemotherapy with HAART has increased remission rates in both HIV-associated Hodgkin and non-Hodgkin lymphoma. 5,6 Recent studies also have confirmed that the International Prognostic Index (IPI) is applicable to patients treated with HAART and chemotherapy. 7 For HIV-infected lymphoma patients with high-risk features as defined by the IPI, relapse rates are still high after conventional chemotherapy. Furthermore, for HIV-infected patients with either relapsed HD or NHL the current salvage chemotherapy regimens offer little chance of long-term survival.In the HIV-negative setting, studies have shown that high-dose therapy with autologous stem cell transplant (ASCT) is the optimal therapy for relapsed HD and NHL. [8][9][10] As the procedure-related mortality of ASCT has decreased, ongoing studies are exploring its use in high-risk first remission patients. 10 Now that HIV-infected individuals have markedly improved immune and hematologic function, the use of both solid organ and ASCT is being explored in patients with underlying immunodeficiency and concomitant malignancy or organ dysfunction. 11-15 Herein we report the City of Hope Comprehensive Cancer Center experience on the largest single institution series of patients with HIV-associated lymphomas undergoing ASCT. Our initial experience demonstrated the feasibility of this approach in terms of stem cell mobilization, engraftment, and low regimen-related toxicity. 16 Now with long-term follow-up in a larger ser...

Treatment of acute lymphoblastic leukemia (ALL) continues to advance, as evidenced by the improved risk stratification of patients and development of newer treatment options. Identification of ALL subtypes based on immunophenotyping and cytogenetic and molecular markers has resulted in the inclusion of Philadelphia-like ALL and early T-cell precursor ALL as subtypes that affect prognosis. Identification of Ikaros mutations has also emerged as a prognostic factor. In addition to improved prognostication, treatment options for patients with ALL have expanded, particularly with regard to relapsed/refractory ALL. Continued development of second-generation tyrosine kinase inhibitors and the emergence of immunotherapy, including blinatumomab and chimeric antigen receptor T-cell therapy, have improved survival. Furthermore, incorporation of minimal residual disease (MRD) monitoring has shown insight into patient outcomes and may lead to treatment modification or alternative treatment strategies in select populations. This excerpt focuses on the sections of the ALL guidelines specific to clinical presentation and diagnosis, treatment of relapsed/refractory ALL, and incorporation of MRD monitoring. To view the most recent complete version of these guidelines, visit NCCN.org. (J Natl Compr Canc Netw 2015;13:1240-1279 NCCN Categories of Evidence and ConsensusCategory 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate. Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. These guidelines are also available on the Internet. For the latest update, visit NCCN.org.

Allogeneic hematopoietic cell transplantation (HCT) is the only known curative modality for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph ؉ ALL). Sixty-seven patients with HLA-matched sibling donors received fractionated total body irradiation (FTBI) and high-dose VP16, whereas 11 patients received FTBI/VP16/cyclophosphamide, and 1 patient received FTBI/VP16/busulfan. The median age was 36 years. At the time of HCT, 49 patients (62%) were in first complete remission (CR1) and 30 patients (38%) were beyond CR1 (> CR1). The median follow-up was 75 months (range, 14-245 months). The 10-year overall survival for the CR1 and beyond CR1 patients was 54% and 29% (P ‫؍‬ .01), respectively, and event-free survival was 48% and 26% (P ‫؍‬ .02), respectively. There was no significant difference in relapse incidence (28% vs 41%, P ‫؍‬ .28), but nonrelapse mortality was significantly higher in the beyond CR1 patients, (31% vs 54%, P ‫؍‬ .03, respectively). By univariate analysis, factors affecting event-free and overall survival were white blood cell count at diagnosis (< 30 ؋ 10 9 /L vs > 30 ؋ 10 9 /L) and disease status (CR1 vs > CR1)

Immunotherapy may potentially improve the outcome of autologous hematopoietic cell transplantation (HCT). Poor effector cell proliferation and marginal antitumor activity limit attempts to use immunotherapy. We have characterized the ex vivo expansion, up to 1000-fold, of CD3+ CD56+ lymphocytes from the peripheral blood lymphocytes (PBL) of healthy donors. Expanded cells termed cytokine-induced killer (CIK) cells induce non-major histocompatibility complex-restricted lysis of tumor cells and demonstrate cytolytic activity superior to lymphokine-activated killer cells without the requirement of interleukin (IL)-2 treatment in vivo. To determine whether cytolytic cells could be expanded from patient material, we evaluated samples of peripheral blood progenitor cells (PBPCs) from 25 patients undergoing autologous HCT. The PBPCs were expanded by priming with interferon-gamma followed by anti-CD3 monoclonal antibody and IL-2 the next day. Fluorescence-activated cell sorting analysis was performed on days 0, 15, 21, and 28 of cell culture. The median T-cell content rose from 15.3% (range, 1.1% to 89.7%) on day 0 to 97.2% (range, 83.6% to 99.5%) by day 15. By day 21, T cells expanded 21.8-fold (range, 1.7- to 420.0-fold) and CD3+ CD56+ cells expanded 44.8-fold (range, 5.1- to 747.0-fold). CIK cells were used as effector cells against B-cell lymphoma targets (OCI-Ly8) with a median of 24% (range, 3% to 67%) and 42% (range, 6% to 96%) specific lysis of target cells on days 21 and 28, respectively. CIK cells derived from PBL of 2 additional patients with acute myelogenous leukemia demonstrated 39% and 78% specific lysis of OCI-Ly8 and 26% and 58% specific lysis of autologous leukemic blasts at an effector:target ratio of 40:1. CIK cells may be expanded from granulocyte colony-stimulating factor-mobilized PBPCs of patients undergoing autologous HCT. CIK cells may provide a potent tool for use in posttransplantation adoptive immunotherapy.