Significant association between tumor mutational burden and immune-related adverse events during immune checkpoint inhibition therapies.

More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.

Reduced-intensity transplantation for lymphomas using haploidentical related donors vs HLA-matched unrelated donors.

We evaluated 917 adult lymphoma patients who received haploidentical (n = 185) or HLA-matched unrelated donor (URD) transplantation either with (n = 241) or without antithymocyte globulin (ATG; n = 491) following reduced-intensity conditioning regimens. Haploidentical recipients received posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis, whereas URD recipients received calcineurin inhibitor-based prophylaxis. Median follow-up of survivors was 3 years. The 100-day cumulative incidence of grade III-IV acute GVHD on univariate analysis was 8%, 12%, and 17% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .44). Corresponding 1-year rates of chronic GVHD on univariate analysis were 13%, 51%, and 33%, respectively (P < .001). On multivariate analysis, grade III-IV acute GVHD was higher in URD without ATG (P = .001), as well as URD with ATG (P = .01), relative to haploidentical transplants. Similarly, relative to haploidentical transplants, risk of chronic GVHD was higher in URD without ATG and URD with ATG (P < .0001). Cumulative incidence of relapse/progression at 3 years was 36%, 28%, and 36% in the haploidentical, URD without ATG, and URD with ATG groups, respectively (P = .07). Corresponding 3-year overall survival (OS) was 60%, 62%, and 50% in the 3 groups, respectively, with multivariate analysis showing no survival difference between URD without ATG (P = .21) or URD with ATG (P = .16), relative to haploidentical transplants. Multivariate analysis showed no difference between the 3 groups in terms of nonrelapse mortality (NRM), relapse/progression, and progression-free survival (PFS). These data suggest that reduced-intensity conditioning haploidentical transplantation with posttransplant cyclophosphamide does not compromise early survival outcomes compared with matched URD transplantation, and is associated with significantly reduced risk of chronic GVHD.

Reduced-Intensity Allografting as First Transplantation Approach in Relapsed/Refractory Grades One and Two Follicular Lymphoma Provides Improved Outcomes in Long-Term Survivors.

This study was conducted to compare long-term outcomes in patients with refractory/relapsed grades 1 and 2 follicular lymphoma (FL) after allogeneic (allo) versus autologous (auto) hematopoietic cell transplantation (HCT) in the rituximab era. Adult patients with relapsed/refractory grades 1 and 2 FL undergoing first reduced-intensity allo-HCT or first autograft during 2000 to 2012 were evaluated. A total of 518 rituximab-treated patients were included. Allo-HCT patients were younger and more heavily pretreated, and more patients had advanced stage and chemoresistant disease. The 5-year adjusted probabilities, comparing auto-HCT versus allo-HCT groups for nonrelapse mortality (NRM) were 5% versus 26% (P < .0001); relapse/progression: 54% versus 20% (P < .0001); progression-free survival (PFS): 41% versus 58% (P < .001), and overall survival (OS): 74% versus 66% (P = .05). Auto-HCT was associated with a higher risk of relapse/progression beyond 5 months after HCT (relative risk [RR], 4.4; P < .0001) and worse PFS (RR, 2.9; P < .0001) beyond 11 months after HCT. In the first 24 months after HCT, auto-HCT was associated with improved OS (RR, .41; P < .0001), but beyond 24 months, it was associated with inferior OS (RR, 2.2; P = .006). A landmark analysis of patients alive and progression-free at 2 years after HCT confirmed these observations, showing no difference in further NRM between both groups, but there was significantly higher risk of relapse/progression (RR, 7.3; P < .0001) and inferior PFS (RR, 3.2; P < .0001) and OS (RR, 2.1; P = .04) after auto-HCT. The 10-year cumulative incidences of second hematological malignancies after allo-HCT and auto-HCT were 0% and 7%, respectively. Auto-HCT and reduced-intensity-conditioned allo-HCT as first transplantation approach can provide durable disease control in grades 1 and 2 FL patients. Continued disease relapse risk after auto-HCT translates into improved PFS and OS after allo-HCT in long-term survivors.

Conditioning regimens for allotransplants for diffuse large B-cell lymphoma: myeloablative or reduced intensity?

The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progression-free survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse.

Successful haematopoietic stem cell transplantation in 44 children from healthy siblings conceived after preimplantation HLA matching.

Haematopoietic stem cell transplantation (HSCT) remains the best therapeutic option for many acquired and inherited paediatric haematological disorders. Unfortunately, the probability of finding an HLA matched donor is limited. An alternative technique is PGD combined with HLA matching, which offers the possibility of selecting unaffected embryos that are HLA compatible with the sick child, with the aim of possible use of stem cells from the resulting baby in future. Since the first successful report for Fanconi anaemia a decade ago, the therapeutic success of this technique was reported in a few cases and for a limited number of disorders. Here, we report full recovery of 44 sick children who received HSCT from healthy infants conceived after pre-implantation HLA matching for the following 10 indications; beta-thalassaemia, Wiskott-Aldrich syndrome, Fanconi anaemia, sickle cell anaemia, acute myeloid leukaemia, acute lymphoblastic leukaemia, Glanzmann's thrombasthaenia, Diamond-Blackfan anaemia, X-linked adrenoleukodystrophy and mucopolysaccharidosis type I. No serious complications were observed among recipients and donors. Graft failure occurred in four children with beta-thalassaemia where a second HSCT was planned. Preimplantation HLA matching is a reliable technique and provides a realistic option for couples seeking treatment for an affected child when no HLA-matched donor is available.

Control of minimal residual cancer by low dose ipilimumab activating autologous anti-tumor immunity.

In this perspective article, we address the controversy regarding the safety-efficacy issue in ipilimumab trials. While the CTLA-4 blockade interrupted T-cell pathways responsible for immune down-regulation and mediated regression of established malignant tumors in a minority of patients, this has to be weighed against the immune related adverse events (irAEs) suffered by the majority. Based on two groundbreaking but neglected proof-of-principle papers that demonstrated augmented graft-vs.-malignancy (GVM) effect that reversed the relapse of malignancy without worsening the graft-vs.-host disease (GVHD) by a CTLA-4 blockade, here we suggest a therapeutic paradigm shift, which may help break the impasse and resolve this timely issue in oncology.

Split immunity: immune inhibition of rat gliomas by subcutaneous exposure to unmodified live tumor cells.

Gliomas that grow uninhibited in the brain almost never metastasize outside the CNS. The rare occurrences of extracranial metastasis are usually associated with a suppressed immune system. This observation raises the possibility that some gliomas might not grow outside the CNS due to an inherent immune response, We report in this study that the highly malignant F98 Fischer rat undifferentiated glioma, which grows aggressively in the brain, spontaneously regresses when injected live s.c. We found that this regression is immune-mediated and that it markedly enhances the survival or cures rats challenged with the same tumor intracranially either before or after the s.c. live-cell treatment. Adoptive transfer experiments showed the effect was immune-mediated and that the CD8 T cell fraction, which exhibited direct tumor cytotoxicity, was more effective than the CD4 T cell fraction in mediating resistance to intracranial challenge of naive rats. Brain tumors from treated rats exhibited enhanced CD3(+)CD8(+)CD4(-) and CD3(+)CD4(+)CD8(-) T cell infiltration and IFN-γ secretion. The results in the F98 glioma were corroborated in the Lewis rat CNS-1 astrocytoma. In both tumor models, s.c. treatment with live cells was significantly better than immunization with irradiated cells. We propose in this study a location-based immunotherapeutic phenomenon we term "split immunity": a tumor that thrives in an immune-privileged site may be inhibited by injecting live, unmodified tumor cells into a site that is not privileged, generating protective immunity that spreads back to the privileged site. Split immunity could explain several long-standing paradoxes regarding the lack of overt extracranial metastasis in patients with primary brain tumors.

Immunotherapy with cure potential of multi-drug resistant hematologic malignancies using IL-2 preactivated intentionally mismatched donor lymphocyte.

PURPOSE: Unfortunately, cure of multi-drug resistant (MDR) hematologic malignancies remains an unmet need. Donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation (SCT) can sometimes eliminate multi-drug resistant leukemia but at a risk of acute and chronic graft-vs-host disease (GVHD) and procedure-related toxicity. Supported by pre-clinical experiments in animal models, we hypothesized that immunotherapy induced by non-engrafting intentionally mismatched IL-2 activated killers (IMAK) including both T & NK cells could induce safer, faster and much more effective immunotherapy while avoiding the need for SCT and the risks of GVHD. METHODS: IMAK treatment was applied in 33 patients with MDR hematologic malignancies conditioned with cyclophosphamide 1000 mg/m2 based protocol. Haploidentical or unrelated donor lymphocytes were preactivated with IL-2 6000 IU/ml for 4 days. IMAK was combined with Rituximab in 12/23 patients with CD20+ B cells. RESULTS: A total of 23/33 patients with MDR (4 failing SCT) achieved complete remission (CR). First patient currently 30 years with no further treatment and 6 observed for > 5 years (2 AML; 2 multiple myeloma, 1 ALL & 1 NHL) can be considered cured. No patient developed > grade 3 toxicity or GVHD. No residual male cells were detectable among six females treated with male cells beyond day + 6, confirming that GVHD was prevented by consistent early rejection of donor lymphocytes. CONCLUSIONS: We hypothesize that safe and superior immunotherapy of MDR with cure potential may be accomplished by IMAK, most probably in patients with low tumor burden, but that remains to be confirmed by future clinical trials.

IL-2-targeted therapy ameliorates the severity of graft-versus-host disease: ex vivo selective depletion of host-reactive T cells and in vivo therapy.

T cell depletion prevents graft-versus-host disease (GVHD) but also removes T cell-mediated support of hematopoietic cell engraftment. A chimeric molecule composed of IL-2 and caspase-3 (IL2-cas) has been evaluated as a therapeutic modality for GVHD and selective ex vivo depletion of host-reactive T cells. IL2-cas does not affect hematopoietic cell engraftment and significantly reduces the clinical and histological severity of GVHD. Early administration of IL2-cas reduced the lethal outcome of haploidentical transplants, and survivor mice displayed markedly elevated levels of X-linked forkhead/winged helix (FoxP3(+); 50%) and CD25(+)FoxP3(+) T cells (35%) in the lymph nodes. The chimeric molecule induces in vitro apoptosis in both CD4(+)CD25(-) and CD4(+)CD25(+) subsets of lymphocytes from alloimmunized mice, and stimulates proliferation of cells with highest levels of CD25 expression. Adoptive transfer of IL2-cas-pretreated viable splenocytes into sublethally irradiated haploidentical recipients resulted in 60% survival after a lethal challenge with lipopolysaccharide, which is associated with elevated fractions of CD25(high)FoxP3(+) T cells in the lymph nodes of survivors. These data demonstrate that ex vivo purging of host-presensitized lymphocytes is effectively achieved with IL2-cas, and that IL-2-targeted apoptotic therapy reduces GVHD severity in vivo. Both approaches promote survival in lethal models of haploidentical GVHD. The mechanism of protection includes direct killing of GVHD effectors, prevention of transition to effector/memory T cells, and induction of regulatory T cell proliferation, which becomes the dominant subset under conditions of homeostatic expansion.

Alternate donor hematopoietic cell transplantation (HCT) in non-Hodgkin lymphoma using lower intensity conditioning: a report from the CIBMTR.

We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range: 18-72 years); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II-IV acute graft-versus-host disease (aGVHD) was 43% at 100 days; and chronic GVHD (cGVHD) was 44% at 3 years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of antithymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use, and chemotherapy resistance were associated with lower PFS. Older age, shorter interval from diagnosis to HCT, non-total body irridiation (TBI) conditioning regimens, ex vivo T cell depletion, and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology, and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT.

Gene therapy for immunodeficiency due to adenosine deaminase deficiency.

BACKGROUND: We investigated the long-term outcome of gene therapy for severe combined immunodeficiency (SCID) due to the lack of adenosine deaminase (ADA), a fatal disorder of purine metabolism and immunodeficiency. METHODS: We infused autologous CD34+ bone marrow cells transduced with a retroviral vector containing the ADA gene into 10 children with SCID due to ADA deficiency who lacked an HLA-identical sibling donor, after nonmyeloablative conditioning with busulfan. Enzyme-replacement therapy was not given after infusion of the cells. RESULTS: All patients are alive after a median follow-up of 4.0 years (range, 1.8 to 8.0). Transduced hematopoietic stem cells have stably engrafted and differentiated into myeloid cells containing ADA (mean range at 1 year in bone marrow lineages, 3.5 to 8.9%) and lymphoid cells (mean range in peripheral blood, 52.4 to 88.0%). Eight patients do not require enzyme-replacement therapy, their blood cells continue to express ADA, and they have no signs of defective detoxification of purine metabolites. Nine patients had immune reconstitution with increases in T-cell counts (median count at 3 years, 1.07x10(9) per liter) and normalization of T-cell function. In the five patients in whom intravenous immune globulin replacement was discontinued, antigen-specific antibody responses were elicited after exposure to vaccines or viral antigens. Effective protection against infections and improvement in physical development made a normal lifestyle possible. Serious adverse events included prolonged neutropenia (in two patients), hypertension (in one), central-venous-catheter-related infections (in two), Epstein-Barr virus reactivation (in one), and autoimmune hepatitis (in one). CONCLUSIONS: Gene therapy, combined with reduced-intensity conditioning, is a safe and effective treatment for SCID in patients with ADA deficiency. (ClinicalTrials.gov numbers, NCT00598481 and NCT00599781.)

Depletion of alloreactive T cells for tolerance induction in a recipient of kidney and hematopoietic stem cell transplantations.

The present case report represents a successful attempt to induce transplantation tolerance to organ allograft by combined administration of donor hematopoietic cells and kidney based on in vivo deletion of alloreactive host-vs-graft and graft-vs-host alloreactive T cells following non-myeloablative conditioning. We were able to induce mixed and eventually full donor chimerism and tolerance of kidney allograft in a 15-yr-old male with ESRD after cisplatin treatment and autologous HSCT for mediastinal germ cell tumor. Our approach to induce tolerance was based on preferential depletion of alloreactive T cells induced by exposure to donor's alloantigens and administration of cyclophosphamide at day 2 and day 3 after stem cell infusion. Additional non-specific immunosuppression as part of the conditioning included exposure to two fractions of TLI, treatment with alemtuzumab (monoclonal anti-CD52) and short-term conventional IS treatment to avoid early graft loss, because of request of IRB. Using this approach, with rapid tapering of all conventional IS treatment, the patient maintains good renal functions without evidence of both acute and chronic rejection for 32 months off all medications.

In vivo T-cell dynamics during immune reconstitution after hematopoietic stem cell gene therapy in adenosine deaminase severe combined immune deficiency.

BACKGROUND: Gene therapy (GT) with hematopoietic stem cells is a promising treatment for inherited immunodeficiencies. OBJECTIVES: Limited information is available on the relative contribution of de novo thymopoiesis and peripheral expansion to T-cell reconstitution after GT as well as on the potential effects of gene transfer on hematopoietic stem cells and lymphocyte replicative lifespan. We studied these issues in patients affected by adenosine deaminase severe combined immune deficiency after low-intensity conditioning and reinfusion of retrovirally transduced autologous CD34(+) cells. METHODS: Immunophenotype, proliferative status, telomere length, and T-cell receptor excision circles were investigated at early and late time points (up to 9 years) after GT treatment. Control groups consisted of pediatric healthy donors and patients undergoing allogeneic bone marrow transplantation (BMT). RESULTS: We observed no telomere shortening in the bone marrow compartment and in granulocytes, whereas peripheral blood naive T cells from both GT and BMT patients showed a significant reduction in telomere length compared with healthy controls. This was in agreement with the presence of a high fraction of actively cycling naive and memory T cells and lower T-cell receptor excision circles. CONCLUSION: These data indicate that T-cell homeostatic expansion contributes substantially to immune reconstitution, like BMT, and is not associated with senescence in the stem cell compartment.

A Clinically Validated, Broadly Active, Oral Viral Superinfection Therapy Could Mitigate Symptoms in Early-stage COVID-19 Patients.

More than 200 viruses infect humans, but treatments are available for less than ten of them. To narrow the gap between 'bugs and drugs,' a paradigm shift is required. The "one drug, one bug" approach can be expanded to a "one drug, multiple bugs" strategy such that the host's defense system is targeted rather than the virus. Viral superinfection therapy (SIT) activates interferon genes' natural, antiviral defense system of host cells following exposure to viral infection, e.g., superinfection with an attenuated infectious bursal disease virus (IBDV) with the release of its double-stranded RNA (dsRNA) cargo inside host cells. An attenuated IBDV therapeutic vaccine has successfully treated hepatitis A virus infection (HAV) in marmoset monkeys as well as acute hepatitis B and hepatitis C virus infections (HBV/HCV) in 42 patients. SIT has also been shown to be safe and effective in four patients with chronic HBV or HCV infection with hepatic decompensation. The proof-of-principle of SIT has also been demonstrated in a 43-year-old male patient with COVID-19. Three doses of orally administered IBDV (3x106 IU) alleviated most of his COVID-19 symptoms; even his sense of smell returned within a week. Two additional COVID-19 patients responded similarly to oral treatment with IBDV. Furthermore, a severe herpes zoster ophthalmicus outbreak with orbital edema responded to a combination of acyclovir and 7 doses of IBDV (7x106 IU) within a few days. IBDV is simple to manufacture and affordable, even in resource-limited settings. Acid-resistant IBDV can be orally administered in an outpatient setting, providing simple dosing and high medication adherence. Under an Emergency Use Authorization, the broad-spectrum IBDV drug candidate could be tested immediately in clinical trials and rapidly distributed to millions of early-stage patients with COVID-19. The German Paul Ehrlich Institute is currently supporting a phase I safety study for persons acutely infected with SARS­CoV-2. An expert team of the US National Institutes of Health-sponsored ACTIV public-private partnership came to the conclusion that the IBDV drug candidate shows merit as a potential treatment for COVID19, and an FDA-approved clinical trial is in the pipelines in Los Angeles.

Allogeneic hematopoietic stem cell transplantation in children and adolescents with recurrent and refractory Hodgkin lymphoma: an analysis of the European Group for Blood and Marrow Transplantation.

Ninety-one children and adolescents 18 years or younger after allogeneic hematopoietic stem cell transplantation (HSCT) for relapsed or refractory Hodgkin lymphoma (HL) were analyzed. Fifty-one patients received reduced intensity conditioning (RIC); 40 patients received myeloablative conditioning (MAC). Nonrelapse mortality (NRM) at 1 year was 21% (+/- 4%), with comparable results after RIC or MAC. Probabilities of relapse at 2 and 5 years were 36% (+/- 5%) and 44% (+/- 6%), respectively. RIC was associated with an increased relapse risk compared with MAC; most apparent beginning 9 months after HSCT (P = .01). Progression-free survival (PFS) was 40% (+/- 6%) and 30% (+/- 6%) and overall survival (OS) was 54% (+/- 6%) and 45% (+/- 6%) at 2 and 5 years, respectively. Disease status at HSCT was predictive of PFS in multivariate analysis (P < .001). Beyond 9 months, PFS after RIC was lower compared with MAC (P = .02). Graft-versus-host disease did not affect relapse rate and PFS. In conclusion, children and adolescents with recurring HL show reasonable results with allogeneic HSCT. Especially patients allografted in recent years with good performance status and chemosensitive disease show highly encouraging results (PFS: 60% +/- 27%, OS: 83% +/- 15% at 3 years). Because relapse remains the major cause of treatment failure, additional efforts to improve disease control are necessary.

Allogeneic hematopoietic stem cell transplantation in ovarian cancer-the EBMT experience.

Although preliminary results suggest that allogeneic hematopoietic stem cell transplantation (allo HCT) for ovarian cancer (OC) is a feasible procedure, the low patient number in previous studies had limited ability to evaluate the true benefit of allo HCT in OC. This retrospective multicenter study included 30 patients with OC allografted between 1995 and 2005 to determine the outcome of patients with OC treated with allo HCT. Prior to allo HCT, patients were in complete response (n = 1), partial response (n = 7), stable disease (n = 11) or had progressive disease (n = 13). An objective response (OR) was observed in 50% (95% CI, 33-67) of patients. Three patients of responding patients had an objective response following the development of acute graft-versus-host disease (aGvHD). The cumulative incidence of chronic GvHD (cGVHD) was 34% (95% CI, 18-50). Transplant relative mortality rates were 7 and 20% on day 100 and 1 year, respectively. With a median follow-up of 74.5 months (range 16-148), median progression free survival (PFS) was 6 months and median overall survival (OS) was 10.4 months. Patients who developed cGvHD following allo HCT had a significant OS improvement compared to those who did not (17.6 months vs. 6.5 months, p = 0.042). However, PFS was not similarly significantly improved in patients who developed cGvHD (12 months versus 3.7 months, p = 0.81). Allo HCT in OC may lead to graft-versus-OC effects. Their clinical relevance remains to be shown.

A comparison of HLA-identical sibling allogeneic versus autologous transplantation for diffuse large B cell lymphoma: a report from the CIBMTR.

We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P < .001), treatment failure (RR 2.06, 95% CI, 1.54-2.75, P < .001), and mortality (RR 2.75, 95% CI, 2.03-3.72, P < .001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73-1.72, P = .59). In fact, for 1-year survivors, no significant differences were observed for TRM, progression, progression-free (PFS) or overall survival (OS). Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT.

Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy.

Gene transfer into HSCs is an effective treatment for SCID, although potentially limited by the risk of insertional mutagenesis. We performed a genome-wide analysis of retroviral vector integrations in genetically corrected HSCs and their multilineage progeny before and up to 47 months after transplantation into 5 patients with adenosine deaminase-deficient SCID. Gene-dense regions, promoters, and transcriptionally active genes were preferred retroviral integrations sites (RISs) both in preinfusion transduced CD34(+) cells and in vivo after gene therapy. The occurrence of insertion sites proximal to protooncogenes or genes controlling cell growth and self renewal, including LMO2, was not associated with clonal selection or expansion in vivo. Clonal analysis of long-term repopulating cell progeny in vivo revealed highly polyclonal T cell populations and shared RISs among multiple lineages, demonstrating the engraftment of multipotent HSCs. These data have important implications for the biology of retroviral vectors, the dynamics of genetically modified HSCs, and the safety of gene therapy.

Immunotherapy in high-risk chemotherapy-resistant patients with metastatic solid tumors and hematological malignancies using intentionally mismatched donor lymphocytes activated with rIL-2: a phase I study.

The feasibility and safety of immunotherapy mediated by intentionally mismatched rIL-2 activated killer lymphocytes (IMAK) with no prior stem cell engraftment was investigated in patients with advanced chemotherapy-resistant hematological malignancies and metastatic solid tumors. Our goals were to maximize anti-cancer activity by using intentionally mismatched donor lymphocytes; amplify killing of target cancer cells by rIL-2 activation of killer cells in vitro and in vivo, and avoid the risk of graft-versus-host disease (GVHD) by anticipated rejection of alloreactive donor lymphocytes. Conditioning consisted of 5 days of fludarabine 25 mg/m(2) or a single dose of cyclophosphamide 1,000 mg/m(2), 2 subcutaneous injections of alpha interferon (IFN) 3 x 10(6) and COX2 inhibitors, followed by administration of IMAK (65 +/- 5 CD3(+)CD56(-); 17 +/- 5 CD3(-)CD56(+)) in conjunction with low dose subcutaneous rIL-2 (6 x 10(6) IU/m(2)/day) for 5 days for continuous activation of alloreactive donor lymphocytes prior to their anticipated rejection. Here, we present our phase 1 clinical study data in a cohort of 40 high-risk patients with metastatic solid tumors and hematological malignancies. Treatment was accompanied by some malaise and occasional self-limited fever but otherwise well tolerated on an outpatient basis. Transient engraftment of donor cells was documented in two patients and only one developed self-limited grade 1 GVHD. Among patients with chemotherapy-resistant disease, long-term progression-free survival was recorded in 5 of 21 evaluable patients with metastatic solid tumors and in four of five patients with hematological malignancies. We conclude that the proposed procedure is feasible, safe, and potentially effective, with some otherwise resistant cancer patients long-term disease-free, thus justifying larger Phase II studies in patients with hematological malignancies and metastatic solid tumors, preferably at a stage of minimal residual disease with the goal in mind to eradicate all malignant cells at an early stage of the disease.

Synthetic, non-natural analogs of ceramide elevate cellular ceramide, inducing apoptotic death to prostate cancer cells and eradicating tumors in mice.

The anticancer effects of synthetic, non-natural analogs of ceramide were tested using human TSU-Pr1 prostate cancer cells in-vitro as well as in-vivo, following their effects on tumors development in mice. When incubated with the cultured cancer cells, the analogs elevated cellular ceramide and induced a cytotoxicity and death by apoptosis. When a ceramide analog was injected intradermally or intraperitoneally into BALB/c-Nude or NOD-SCID mice bearing a human prostate tumor, a considerable regression of the tumor was observed. The synthetic ceramide analogs should thus be further investigated as potential anticancer drugs.