Chimeric antigen receptor (CAR) T cells are a promising therapy for hematologic malignancies. B-cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM).
We conducted a phase I ...study of autologous T cells lentivirally-transduced with a fully-human, BCMA-specific CAR containing CD3ζ and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts: 1) 1-5 x 108 CART-BCMA cells alone; 2) Cyclophosphamide (Cy) 1.5 g/m2 + 1-5 x 107 CART-BCMA cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART-BCMA cells. No pre-specified BCMA expression level was required.
CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe CRS and encephalopathy. Responses (based on treated subjects) were seen in 4/9 (44%) in cohort 1, 1/5 (20%) in cohort 2, and 7/11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4:CD8 T cell ratio and frequency of CD45RO-CD27+CD8+ T cells in the pre-manufacturing leukapheresis product.
CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily-pretreated MM patients.
NCT02546167.
University of Pennsylvania-Novartis Alliance and NIH.
Chimeric antigen receptor (CAR) T cells have demonstrated promising efficacy, particularly in hematologic malignancies. One challenge regarding CAR T cells in solid tumors is the immunosuppressive ...tumor microenvironment (TME), characterized by high levels of multiple inhibitory factors, including transforming growth factor (TGF)-β. We report results from an in-human phase 1 trial of castration-resistant, prostate cancer-directed CAR T cells armored with a dominant-negative TGF-β receptor (NCT03089203). Primary endpoints were safety and feasibility, while secondary objectives included assessment of CAR T cell distribution, bioactivity and disease response. All prespecified endpoints were met. Eighteen patients enrolled, and 13 subjects received therapy across four dose levels. Five of the 13 patients developed grade ≥2 cytokine release syndrome (CRS), including one patient who experienced a marked clonal CAR T cell expansion, >98% reduction in prostate-specific antigen (PSA) and death following grade 4 CRS with concurrent sepsis. Acute increases in inflammatory cytokines correlated with manageable high-grade CRS events. Three additional patients achieved a PSA reduction of ≥30%, with CAR T cell failure accompanied by upregulation of multiple TME-localized inhibitory molecules following adoptive cell transfer. CAR T cell kinetics revealed expansion in blood and tumor trafficking. Thus, clinical application of TGF-β-resistant CAR T cells is feasible and generally safe. Future studies should use superior multipronged approaches against the TME to improve outcomes.
A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after ...myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.).
We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet ...hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.
This study in patients with relapsed, refractory, or high-risk multiple myeloma (MM) evaluated the safety and activity of autologous T cells engineered to express an affinity-enhanced T-cell receptor ...(TCR) that recognizes a peptide shared by cancer antigens New York esophageal squamous cell carcinoma-1 (NY-ESO-1) and L-antigen family member 1 (LAGE-1) and presented by HLA-A*02:01. T cells collected from 25 HLA-A*02:01-positive patients with MM expressing NY-ESO-1 and/or LAGE-1 were activated, transduced with self-inactivating lentiviral vector encoding the NY-ESO-1c259TCR, and expanded in culture. After myeloablation and autologous stem cell transplant (ASCT), all 25 patients received an infusion of up to 1 × 1010 NY-ESO-1 specific peptide enhanced affinity receptor (SPEAR) T cells. Objective response rate (International Myeloma Working Group consensus criteria) was 80% at day 42 (95% confidence interval CI, 0.59-0.93), 76% at day 100 (95% CI, 0.55-0.91), and 44% at 1 year (95% CI, 0.24-0.65). At year 1, 13/25 patients were disease progression-free (52%); 11 were responders (1 stringent complete response, 1 complete response, 8 very good partial response, 1 partial response). Three patients remained disease progression-free at 38.6, 59.2, and 60.6 months post-NY-ESO-1 SPEAR T-cell infusion. Median progression-free survival was 13.5 months (range, 3.2-60.6 months); median overall survival was 35.1 months (range, 6.4-66.7 months). Infusions were well tolerated; cytokine release syndrome was not reported. No fatal serious adverse events occurred during study conduct. NY-ESO-1 SPEAR T cells expanded in vivo, trafficked to bone marrow, demonstrated persistence, and exhibited tumor antigen-directed functionality. In this MM patient population, NY-ESO-1 SPEAR T-cell therapy in the context of ASCT was associated with antitumor activity. This trial was registered at www.clinicaltrials.gov as #NCT01352286.
•Receptor-engineered T-cell therapy has good efficacy and acceptable safety in advanced myeloma in the context of SCT.•Engineered T cells expanded, trafficked to bone marrow, persisted, and exhibited functionality; were associated with a clinical response.
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Introduction: Tisagenlecleucel (CTL019, tisa-cel) was recently approved for treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), high grade B cell lymphoma (r/r HGBCL), and ...transformed follicular lymphoma (r/r tFL) after second line therapy. Prior to tisa-cel release for commercial use in the United States (US), the final manufactured, patient-specific product must meet specific Lot Release Specifications including requirements that the product's dose contains 0.6 to 6.0 x 108 CAR-positive viable T cells and total cell viability is at least 80%. CAR T cell products that do not meet predetermined release specifications are considered “out of specification” (OOS) and may only be administered via an expanded access protocol or a single patient IND. To date, there are no prospectively reported data with regard to the reasons that commercially manufactured CTL019 products are OOS or clinical outcomes after infusion of OOS CTL019 products.
Methods: We are participating in a prospective, managed access protocol to allow administration of CTL019 to patients (pts) with r/r aggressive B-cell lymphomas meeting the approved prescribing information who are intended for treatment with US commercial tisa-cel but have OOS products. Pts were provided product via this managed access program and consent was obtained from all pts enrolled. Pts were unable to receive commercially manufactured product due to failure of apheresis material to meet acceptance specifications, failure of final manufactured product to meet the commercial release specifications, or failure to meet other product specifications within the prescribing information (e.g., interferon gamma release testing). Response was assessed at 3 months post CTL019 infusion by 2014 Lugano Classification criteria applied to FDG-PET/CT imaging. Adverse events were defined by CTCAE and ASTCT criteria.
Results: From 9/2018 to 7/2019, 16 pts were enrolled at our institution. Nine pts were diagnosed with r/r DLBCL, 5 pts had r/r HGBCL, and 2 pts had r/r tFL; 44% of all pts had “double-hit” lymphoma. Median age at CTL019 infusion was 68 years (range: 42-75 years); 7 pts (44%) were female. Twelve pts (75%) had advanced stage lymphoma at leukapheresis. Median prior therapies before leukapheresis was 3 (range: 2-5). Median ECOG performance status was 0 (range: 0-2). Median absolute lymphocyte count and CD3 count were 900/uL (range: 200-1300/uL) and 614/uL (range: 228-1343/uL), respectively. Median CTL019 dose was 1.3 x 108 CAR-positive viable T cells (range: 0.5 x 108 to 2.1 x 108). Median product viability was 78.4% (range: 70.8-87.4%). Thirteen of 16 pts (81%) were enrolled due to low viability products (viability < 80%). The median viability for pts enrolled due to low product viability was 78.0% (range: 70.8-79.8%). The remaining 3 pts' products did not meet release specifications due to T cell dose below 0.6 x 108 CAR-positive T cells (dose administered, 0.5 x 108; n=1), residual beads by microscopy (n=1), or IFN gamma release level above the upper range (>1000 fg/transduced cell; n=1). All pts with low viability products had CAR-positive T cell doses that were within the product dose specifications for tisa-cel (13 of 13 pts).
Of 16 pts enrolled, 11 pts have at least 3 months follow-up; 3 pts were never treated due to progressive lymphoma and 2 pts have not had 3 month response assessments. Median follow-up is 3.4 months. There were 3 pts with CRS grades 1 or 2 by ASTCT criteria and no pts had neurotoxicity. Of 3 pts with CRS, one received a low dose of CTL019 (grade 2 CRS), one had higher levels of IFN gamma (grade 1 CRS), and one had low viability (grade 1 CRS). For all pts infused with OOS products, the 3-month overall response rate (ORR) was 64% including 6/11 (55%) CR and 1/11 (9%) PR. Progression-free survival (PFS) is 64% at 3 months (median not reached, 95%CI: 30-85%). For OOS products due to low viability, ORR was 4/8 (50%) CR and 4/8 (50%) PD; 3-month PFS was 50% (95%CI: 15-77%).
Conclusions: We report the first experience with commercially produced CTL019 products that do not meet product release specifications, primarily due to low viability. Three-month ORRs appear similar to published tisa-cel outcomes for aggressive B-cell non-Hodgkin lymphomas. Our results suggest that other product release characteristics such as potency and replicative capacity should also be more carefully evaluated prior to establishing criteria for release.
Chong:Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Porter:Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Barta:Merck: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Mundipharma: Honoraria. Levine:Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy; CRC Oncology: Consultancy; Cure Genetics: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Avectas: Membership on an entity's Board of Directors or advisory committees. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria.
Out of specificity product release of tisagenlecleucel
Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present ...on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019).
Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS).
ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently.
CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells.
Clinicaltrials.gov identifier NCT02135406.
Novartis, NIH, Conquer Cancer Foundation.
BACKGROUND. CAR T cells are a promising therapy for hematologic malignancies. B cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS. We conducted a phase I study of ...autologous T cells lentivirally transduced with a fully human, BCMA-specific CAR containing CD3Z and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts as follows: cohort 1, 1 x 108 to 5 x 108 CART-BCMA cells alone; cohort 2, cyclophosphamide (Cy) 1.5 g/ m2 plus 1 x 107 to 5 x 107 CART-BCMA cells; cohort 3, Cy 1.5 g/m2 plus 1 x 108 to 5 x 108 CART-BCMA cells. No prespecified BCMA expression level was required. RESULTS. CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe cytokine release syndrome and encephalopathy. Responses (based on treated subjects) were seen in 4 of 9 (44%) in cohort 1, 1 of 5 (20%) in cohort 2, and 7 of 11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4/CD8 T cell ratio and frequency of CD45RO-CD27·CD8· T cells in the premanufacturing leukapheresis product. CONCLUSION. CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily pretreated patients with MM.
Background: CART-BCMA is an autologous T cell product engineered by lentiviral transduction to express a fully human BCMA-specific CAR with CD3ζ and 4-1BB signaling domains and expanded ex vivo using ...anti-CD3/anti-CD28 beads. We reported early safety and clinical activity of CART-BCMA without lymphodepleting chemotherapy in highly refractory MM patients (pts) (Cohen et al, ASH 2016, #1147). Here we report extended results from this initial cohort, as well as initial safety and efficacy in additional cohorts at 2 dose levels in conjunction with cyclophosphamide (Cy). Methods: Three cohorts are being enrolled: 1) 1-5 x 108 CART cells alone; 2) Cy 1.5 g/m2 + 1-5 x 107 CART cells; and 3) Cy 1.5 g/m2 + 1-5 x 108 CART cells. CART-BCMA cells are given as split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2), with Cy given on day -3. Pts need serum creatinine (Cr) <2.5 mg/dL or Cr clearance ≥30 ml/min; adequate hepatic, cardiac, and pulmonary function; and absolute CD3 count ≥150/µL. BCMA expression on MM cells is assessed but not required for eligibility. CART-BCMA expansion/persistence is assessed by flow cytometry and qPCR. Soluble BCMA levels are measured by ELISA. Responses are assessed by IMWG criteria. Results: As of 7/24/17, 33 pts have consented, with 28 eligible, 21 infused, 4 awaiting infusion, and 3 manufactured but never treated due to rapid progression/clinical deterioration. Of treated patients (n=21), 9 are in Cohort 1, 5 in Cohort 2, and 7 in Cohort 3. Median age is 57 (range 44-73); 71% male; median 4.3 years from diagnosis. Median lines of therapy is 7 (range 3-11); 100% are proteasome inhibitor and IMID-refractory, 67% daratumumab-refractory. 95% had high-risk cytogenetics, 67% del17p or TP53 mutation; 29% extramedullary disease. All expressed BCMA on MM cells and received the minimum target dose of CART-BCMA, with 18 pts (86%) receiving full planned dose, and 3 pts receiving 40% of dose (3rd infusion held due to fevers). Toxicities in Cohort 1 (n=9) were previously reported, and included cytokine release syndrome (CRS) in 8 pts (3 grade 3/4, with 4 receiving tocilizumab) and neurotoxicity (grade 4 encephalopathy) in 2 pts. In Cohorts 2 and 3 (n=12), CRS has occurred in 9 pts (3 grade 3, 0 grade 4, none requiring tocilizumab), and neurotoxicity in 1 pt (grade 2 confusion/aphasia), with no unexpected/dose-limiting toxicities, and no treatment-related deaths. Regarding efficacy, in Cohort 1 6/9 pts responded (1 sCR, 2 VGPR, 1 PR, 2 MR), with 1 ongoing sCR at 21 months, and other responses lasting 1.5 to 5 months. In Cohort 2, with Cy but 10-fold lower CART dose, 2/5 pts responded (1 PR, 1 MR) but progressed at 4 and 2 months, respectively. In cohort 3, median follow-up is currently 1 month, with 5/6 pts responding (1 CR, 3 PR, 1 MR) and 1 not yet evaluable. All pts had detectable CART-BCMA expansion by qPCR, and 90% were detectable by flow cytometry, with preferential expansion of CD8+ cells, and similar degree of expansion in blood and marrow. Median peak expansion (as measured by copies/µg DNA) is 6160, 14761, and 45268 in Cohorts 1, 2, and 3, respectively, suggesting a benefit with adding Cy, though this was not statistically significant. Achieving PR or better is associated with higher peak CART-BCMA levels and decline in soluble BCMA, but not with baseline soluble BCMA level or intensity of baseline BCMA expression by flow on MM cells. Serial marrow flow cytometry demonstrates that 5/6 pts with ≥PR and detectable residual MM cells have decreased BCMA intensity on MM cells post-infusion compared with baseline. Conclusions: CART-BCMA infusions following Cy lymphodepletion are feasible and have significant clinical activity in highly-refractory MM pts with poor-risk genetics and limited treatment options. Efficacy appears lower at the 107 dose, compared with 108, and remaining pts are now being enrolled in Cohort 3. CRS remains a common but manageable toxicity. Decreased BCMA expression on residual MM cells post-infusion may be an escape mechanism reflecting CART-BCMA-induced immune editing. These data provide further support for exploration of CART-BCMA in relapsed/refractory MM, with updated cohort 3 data to be presented at the meeting.
Cohen:Bristol Meyers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Lacey:Novartis: Research Funding; Genentech: Honoraria. Lancaster:Amgen: Consultancy; Janssen: Consultancy. Vogl:Karyopharm: Consultancy; Amgen: Consultancy; Teva: Consultancy; Calithera: Research Funding; GSK: Research Funding; Celgene: Consultancy; Takeda: Consultancy, Research Funding; Constellation: Research Funding. Weiss:Prothena: Research Funding; Alnylam: Honoraria; Janssen: Honoraria; Janssen: Research Funding; Prothena: Honoraria. Chen:Novartis: Research Funding. Young:Novartis: Research Funding. Richardson:Novartis: Employment. Isaacs:Novartis Pharmaceuticals: Employment. Melenhorst:Novartis: Research Funding. Levine:GE Healthcare: Consultancy; Tmunity Therapeutics: Equity Ownership, Research Funding; Brammer Bio: Consultancy; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding; Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Milone:Novartis: Patents & Royalties.
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Background: Despite major advances in the treatment of multiple myeloma (MM) only a minority of patients achieve long-term disease control. Immunotherapy combined with autologous hematopoietic stem ...cell transplantation (auto-HCT) may reduce relapse rates. Vaccination with Ig idiotype (Id) conjugated with a carrier protein, keyhole limpet hemocyanin (KLH), was associated with superior disease-free survival in a randomized trial in follicular lymphoma (Schuster S. et al. JCO 2011), and Id is also a tumor-specific antigen in MM. In addition, anti-CD3/-CD28 costimulated adoptive T-cell transfer augmented immune responses to pneumococcal vaccination despite cytotoxic therapy (Rapoport A et al. Nat Med 2005). We therefore hypothesized that Id-KLH vaccine + the vaccine-primed costimulated T cells will result in a robust Id-specific humoral and cellular response, compared with control vaccine (KLH only).
Methods: In this randomized, phase II trial, eligible patients were randomized 1:1 to receive either KLH-only or Id-KLH vaccine, followed by auto-HCT, and then vaccine- primed costimulated T cells followed by two booster doses of the vaccine to which they were randomized. Immune response (IR) was evaluated by gene expression profiling (GEP) using NanoString nCounter.
Results: A total of 36 patients were enrolled between 1/2013 and 5/2015, 20 to KLH-only and 16 to Id-KLH arm, and completed their assigned treatments. There were no significant differences between the groups in age, gender, stage, cytogenetic risk, induction regimen or response to induction (Table). Nineteen (95%) and 16 (100%) patients received maintenance therapy after protocol treatment in KLH-only and Id-KLH, respectively (p=0.42). No infusion reactions or dose-limiting toxicity was seen in either arm. There was no non-relapse mortality at 100-day and 1-year in either arm. At last evaluation, 5 (25%) and 7 (44%) had achieved CR in KLH-only and Id-KLH, respectively (p=0.29). Six (30%) and 9 (56%) achieved at least nCR in KLH-only and Id-KLH, respectively (p=0.17), and 12 (60%) and 12 (75%) achieved at least a VGPR in KLH-only and Id-KLH, respectively (0.48). Ten (50%) and 8 (50%) patients, for whom there were sufficient samples available underwent IR analysis in KLH-only and Id-KLH, respectively at baseline and at 30, 90 and 180 days after activated T cell infusion. In an initial 568 gene panel analyzed for IR, compared with KLH-only, there was a greater change in IR genes in CD8+ T cells in Id-KLH at days 30, 90 and 180 (Figure 1A). In a 30-gene panel of the most upregulated IR genes in CD8+ cells, there was a significantly higher expression of these genes in Id-KLH at all post-treatment time points (Figure 1B). Specifically, at day 180 post-treatment, there was higher expression of immune co-stimulatory genes in Id-KLH in both CD8+ and CD4+ T cell subsets. This increased co-stimulatory gene expression in Id-KLH vaccinated CD4+ (Figure 1C) and CD8+ T cells (not shown) was most marked in patients who had achieved a CR. After a median follow up of 38.3 months, 3-year PFS in KLH-only and Id-KLH was 64% and 53%, respectively (p=0.25).
Conclusion: Id-KLH vaccine and vaccine-primed costimulated T cells can be safely administered in the setting of auto-HCT. In this randomized trial we detected a trend towards a deeper clinical response in the Id-KLH arm. There were significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm,which also correlated withdepth of clinical response. Future trials should focus on selection of patients most likely to mount a robust IR to Id vaccines.
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Shah:TeneoBio, Inc.: Honoraria; Indapta Therapeutics: Other: Stock Ownership; Celgene: Research Funding; Celgene, Indapta Therapeutics, Takeda: Consultancy. Patel:Juno: Consultancy; Celgene: Consultancy; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thomas:Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Orlowski:BioTheryX: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cohen:Celgene: Consultancy; Bristol Meyers Squibb: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Janssen: Consultancy. Vogl:Constellation: Research Funding; Karyopharm: Consultancy; GSK: Research Funding; Calithera: Research Funding; Takeda: Consultancy, Research Funding; Teva: Consultancy; Amgen: Consultancy; Celgene: Consultancy. June:Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kwak:Celltrion, Inc: Consultancy; InnoLifes: Consultancy, Equity Ownership; Pepromene Bio: Consultancy, Equity Ownership.
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