Allogeneic hematopoietic stem cell transplants (alloHSCT) remain the only curative treatment for many hematologic malignancies; however, they are associated with significant toxicity. Strategies to ...maintain graft-versus-tumor (GvT) and graft-versus-leukemia (GvI) effects while eliminating GvHD have long been a goal of the field. Orca-T is a high-precision cell therapy, consisting of stem and immune cells, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses.
As of 10/25/2022, 151 patients had received Orca-T and had ≥ 100 days of follow-up (f/u). These patients had AML (44%), ALL (31%), MPAL (3%), CML w/prior blast crisis (5%), or high-risk MDS (15%), and were in CR. Median f/u was 15 months (range 3-43). Patients were aged 19-71 (median 48); 57% male. Donors were HLA-matched related (52%) or unrelated (48%). Patients received MAC regimens prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus (n=148) or sirolimus (n=3). For comparison, an independent CIBMTR-based cohort was identified which consisted of patients (AML, ALL, or MDS) who received MAC alloHSCT with PBSC source between 2016-2018 followed by tacrolimus/methotrexate prophylaxis.
Orca-T was successfully manufactured in a single, centralized GMP manufacturing facility, distributed, and infused throughout the U.S. GRFS and OS was 70% and 88% in the Orca-T population compared to 21% and 68%, at 1 year, in the CIBMTR cohort, respectively. Non-relapse mortality (NRM) with Orca-T was 4% compared to 10%, at 1 year, in CIBMTR. Median times to neutrophil and platelet engraftment for Orca-T were 13 and 16 days, respectively; graft failure was 1.6%. Clinical outcomes with Orca-T appeared to be enhanced with a conditioning regimen of busulfan, fludarabine, and thiotepa (n=71 patients). RFS and NRM were 87% and 0% at 1 year, respectively. Grade ≥ 3 aGvHD and moderate-to-severe cGvHD rates were 1.5% and 5%, respectively. GRFS was 81% and OS was 94% at one year.
At more than 1 year of median f/u, outcomes with Orca-T demonstrate robust GvT and GvI effects while markedly reducing GvHD and NRM despite MAC. A multi-center randomized controlled phase 3 trial comparing Orca-T to SOC is currently enrolling across the US (NCT05316701).
Background: Autologous stem cell transplantation (ASCT) is a curative therapy for a significant proportion of patients with relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We previously ...developed a conditioning regimen for R/R cHL patients undergoing ASCT incorporating gemcitabine and vinorelbine (GN-BVC), which enabled a reduction in the BCNU dose and toxicity without compromising efficacy (BBMT 2010;16:1145-54). Since this publication, several novel agents have been approved for treatment of R/R cHL including brentuximab vedotin (BV) and the immune checkpoint inhibitors (ICIs), which may be changing outcomes and toxicities following ASCT. We sought to determine whether post-ASCT outcomes have improved for R/R cHL in the era of novel agents, and to evaluate how BV and the ICIs have impacted toxicities after ASCT in a large cohort of patients treated with the same conditioning regimen.
Methods: We conducted a single-center, retrospective analysis of outcomes for a large cohort of patients with R/R cHL who underwent ASCT using GN-BVC conditioning at Stanford University from 2001-2017 (n=268). We divided the cohort into two treatment eras: Era A: 2001-2009 (n=137) and Era B (increasing use of novel agents): 2010-2017 (n=131). We used Kaplan-Meier and Cox models to compare overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) between treatment eras. We also compared outcomes between patients who underwent ASCT in complete remission (CR, n=126) or with a partial response (PR, n=142). For patients treated in era B, we compared outcomes and toxicity profiles for patients treated with standard platinum-based salvage regimens (n=102) to those who received BV-based salvage regimens prior to ASCT (n=29).
Results: Patients who underwent ASCT in era B had improved OS compared to those transplanted in era A (4-year OS: 87.8% vs 77.9%, HR 0.51, 95% CI 0.28-0.91, p=0.022), but PFS did not differ significantly between treatment eras (4-year PFS: 70.2% vs 62.7%, HR 0.78, 95% CI 0.52-1.2, p=0.24, Figure 1). For patients who relapsed after ASCT, PPS was significantly higher for those transplanted in era B compared to era A (84.7% vs 62.8% at 2 years, HR 0.47, 95% CI 0.23-0.98, p=0.045). Overall, patients who underwent ASCT in CR compared to those with a PR had significantly improved OS (88.3% vs 78.3% at 4 years, HR 0.50, 95% CI 0.29-0.88, p=0.016) and PFS (78.4% vs 55.1% at 4 years, HR 0.44, 95% CI 0.28-0.67, p=0.00016). Among patients who relapsed, those in era B who received novel agents (BV and/or an ICI) at any point in treatment exhibited higher OS compared to historical controls in era A (4-year OS: 72.2% vs 53.1%) but were statistically different only at the p=0.083 level which is above the p=0.05 significance threshold.
Of the patients who underwent ASCT in era B (n=131), 102 (78%) received standard platinum-based salvage regimens (e.g. ICE or DHAP) and 29 (22%) received BV-based salvage regimens prior to ASCT, including 11 patients (8%) who received both BV and an ICI pre-ASCT. Outcomes were excellent for patients who received BV-based salvage regimens pre-ASCT (4-year OS 97% and PFS 76%) but were not statistically different compared to patients who received platinum-based regimens (4-year OS 86% and PFS 69%; p=0.56 and p=0.76, respectively). Pneumonitis requiring corticosteroids occurred in 8% of patients treated in era B, including 10% of patients receiving BV-based salvage regimens pre-ASCT and 7% of patients receiving standard platinum-based regimens. One patient who received BV and nivolumab pre-ASCT died from grade 5 pneumonitis.
Conclusions: In this cohort of R/R cHL patients who underwent ASCT using the same conditioning regimen, OS was significantly higher for patients transplanted within the past decade. A potential survival benefit was observed among patients who relapsed post-ASCT, likely reflecting the more widespread use of BV and ICIs in the post-ASCT setting. Patients who received BV-based salvage regimens pre-ASCT had excellent outcomes without an apparent increase in toxicity, but the small number of patients limits comparisons to standard platinum-based regimens. Further studies are needed to better define the optimal sequencing of novel agents and ASCT in the treatment of R/R cHL in the modern era.
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Sica:Physician's Education Resources (PER): Honoraria. Advani:Celgene: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cell Medica, Ltd: Consultancy; Kyowa Kirin Pharmaceutical Developments, Inc.: Consultancy; Regeneron: Research Funding; Celmed: Consultancy, Membership on an entity's Board of Directors or advisory committees; Stanford University: Employment, Equity Ownership; Seattle Genetics: Consultancy, Research Funding; Agensys: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kura: Research Funding; Merck: Research Funding; Infinity Pharma: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences, Inc./Kite Pharma, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Forty-Seven: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Miklos:AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Muffly:Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Rezvani:Kaleido: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; Nohla Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: one-time compensation from advisory boards; AbbVie: Other: Principal investigator ; U.S. Department of Justice: Other: Expert medical witness; Johnson & Johnson: Employment, Other: Brother is employed. Shizuru:Forty Seven Inc: Equity Ownership, Patents & Royalties.
The immunosuppressive effects of total lymphoid irradiation (TLI) for protection against graft-versus-host disease (GvHD) after allogeneic bone marrow transplantation have been studied for years in ...animal models. In preclinical models of bone marrow transplantation non-myeloablative TLI conditioning protects against GvHD by skewing host T-cell subsets to favor regulatory natural killer T cells that suppress GvHD by polarizing donor T cells towards secretion of non-inflammatory cytokines such as IL-4. These preclinical models have recently been adapted to human transplantation.
Patients receiving allogeneic hematopoietic cell transplantation for hematological malignancies conditioned with TLI and depletive T-cell antibodies showed sustained donor chimerism, a reduced incidence of acute GvHD yet retained anti-tumor activity. As in the preclinical models, the low incidence of GvHD is associated with increased IL-4 secretion by chimeric donor T cells.
This review summarizes the evolution of the preclinical TLI protocols and their recent translation to clinical trials, and discusses the mechanisms involved in protection from GvHD and the induction of tolerance following mixed chimerism.
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia in Western countries, and there is significant variability in survival within CLL clinical stages. Earlier studies showed ...that CLL cells produce and are usually growth inhibited by transforming growth factor β type 1 (TGF-β 1), suggesting a mechanism for the clinically indolent course of most CLL. Here we studied the mechanism by which CLL cells from about one-third of the patients are insensitive to TGF-β 1. Of the 13 patients studied, CLL cells isolated from the peripheral blood of 8 patients were sensitive to growth inhibition by TGF-β 1, as determined by incorporation of tritiated thymidine, whereas those from 5 patients were completely resistant to TGF-β 1. As judged by binding of radiolabeled TGF-β 1 followed by cross-linking and immunoprecipitation with anti-receptor antisera, CLL cells sensitive to TGF-β 1 exhibited normal cell surface expression of both types 1 and 2 TGF-β receptors. In contrast, all CLL cells resistant to TGF-β 1 exhibited no detectable surface type I receptors able to bind TGF-β 1, but normal expression of type II receptors. Both TGF-β 1-sensitive and TGF-β 1-resistant CLL cells contained normal amounts of both type 1 and type 2 receptor mRNAs. Specific loss of type 1 receptor expression represents a new mechanism by which cells acquire resistance to TGF-β 1-mediated growth inhibition in the development and progression of human lymphoproliferative malignancies.
A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing ...residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)–matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.
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