BI 836909 is a Bispecific T cell Engager (BiTE), designed to redirect the body’s endogenous T cells towards cells expressing B cell maturation antigen (BCMA) on the cell surface (Presentation, ASH (Free ASH Whitepaper), DEC 6, 2015, View Source [SID:1234510960]).
BCMA is a highly plasma cell specific antigen and shows homogeneous expression on the cell surface of multiple myeloma, plasma cell leukemia and plasmacytoma cells. In normal tissues, BCMA expression is restricted to plasma cells, while other normal tissues do not express BCMA. This highly selective expression pattern makes BCMA an ideal target for T cell redirecting therapy.

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The pharmacological effect of BI 836909 depends on its simultaneous binding to both the CD3 epsilon subunit of the T cell receptor complex on T cells as well as to BCMA on multiple myeloma cells, resulting in the lysis of the BCMA-expressing cells.

In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several multiple myeloma cell lines and increasing concentrations of BI 836909, and tumor cell lysis, T cell activation, and induction of cytokine release were assessed. BI 836909 induced dose-dependent redirected lysis of human multiple myeloma cell lines with EC90 values ranging from 16 to 810 pg/mL. Viability of BCMA-negative cells was not affected, demonstrating the specificity of BI 836909 for BCMA. The expression of the activation markers CD69 and CD25 on T cells and the release of cytokines by T cells were target-dependent and occurred only in the presence of BCMA-positive cells.

In vivo anti-tumor activity of BI 836909 was assessed in NOD/SCID mice reconstituted with human T cells and bearing subcutaneous or orthotopic xenografts derived from human multiple myeloma cell lines.

In the subcutaneous NCI-H929 xenograft model, animals were treated with BI 836909 by daily intravenous or subcutaneous bolus injections. Statistically significant dose-dependent anti-tumor activity was observed at doses of 50 µg/kg/day and higher. The efficacy of BI 836909 was comparable after intravenous and subcutaneous administration, when the difference in bioavailability of the different routes was considered.

In an orthotopic L-363 xenograft model, treatment with BI 836909 resulted in a statistically significant prolonged survival at doses of 5 µg/kg/day and higher.

BI 836909 shows comparable cross-reactive binding to both BCMA and CD3 epsilon of human and macaque origin at picomolar and low nanomolar affinities respectively, thus allowing the assessment of pharmacodynamics, pharmacokinetics, and safety in non-human primates. In toxicity studies, cynomolgus monkeys were administered doses of up to 135 µg/kg/day of BI 836909 via continuous intravenous infusion, and up to 405 µg/kg/day via daily subcutaneous injection for up to 28 days. A dose- dependent decrease in plasma cells was observed in the bone marrow of treated animals compared to the vehicle control group, consistent with BCMA expression on cynomolgus monkey plasma cells, this demonstrated the pharmacological activity of BI 836909.

These pre-clinical data demonstrate that BI 836909 is a highly potent, efficacious and BCMA-selective T cell redirecting agent and support clinical testing of BI 836909 in multiple myeloma patients.

On December 6, 2015 Curis, Inc. (NASDAQ:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, reported data from the completed dose escalation and ongoing expansion stages of the Phase 1 trial of CUDC-907, an oral dual inhibitor of histone deacetylase (HDAC) and phosphoinositide 3-kinase (PI3K) enzymes (Press release, Curis, DEC 6, 2015, View Source [SID:1234508438]). These data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper)’s (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, FL. The data demonstrated that treatment with CUDC-907 resulted in complete (CRs) and partial responses (PRs) in heavily pretreated patients with relapsed/ refractory diffuse large B cell lymphoma (RR-DLBCL), including those harboring alterations of the MYC oncogene, a poor performing sub-group for which there are no approved targeted therapies.

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In the ongoing Phase 1 trial of CUDC-907, 8 objective responses (3 CRs and 5 PRs) were reported in 18 response-evaluable patients out of a total of 25 patients with RR-DLBCL enrolled in the trial. These results include 1 CR among 2 response-evaluable patients out of a total of 3 patients treated with CUDC-907 in combination with the standard dose of rituximab. The remaining 16 evaluable patients were treated with CUDC-907 monotherapy. In a retrospective post hoc analysis, among the 8 patients who achieved objective responses, 5 had tumors with MYC oncogene alterations (defined as chromosome translocation involving MYC gene locus, gain in MYC gene copy number, or MYC protein over-expression in =40% tumor cells). Among the remaining 3 patients who achieved objective responses, 2 had MYC protein expression in less than 40% of tumor cells, and the third patient’s MYC status is unknown.

In preclinical studies, CUDC-907 treatment of DLBCL cell lines was shown to result in complete suppression of MYC protein levels in a rapid and dose dependent manner. Additionally, anti-tumor activity was observed in multiple in vivo MYC-altered DLBCL models.

"Preliminary data for CUDC-907 in patients with multiply relapsed DLBCL appear encouraging, even in those with MYC-altered lymphoma, providing the rationale for further investigation in a Phase 2 trial," said Dr. Anas Younes, MD, Chief of the Lymphoma Service of the Memorial Sloan Kettering Cancer Center in New York City and the Principal Investigator of the Phase 1 trial. "There is a high unmet need for novel therapies for patients with RR-DLBCL, and particularly for the subset of patients with MYC-altered DLBCL due to their poor prognosis."

Based on promising clinical activity observed in patients with RR-DLBCL, particularly those with cancers harboring MYC alterations, Curis expects to initiate a Phase 2 trial to examine CUDC-907 in patients with MYC-altered DLBCL. In this trial, approximately 120 patients with relapsed/refractory disease will be randomly assigned to receive CUDC-907 as monotherapy or CUDC-907 with the standard dose of rituximab. Patients will remain on treatment until progression of disease, discontinuation for safety reasons, or other reasons for treatment discontinuation. The primary endpoint of the trial is objective response rate with secondary endpoints that include progression free survival, overall survival and duration of response. Positive results with CUDC-907 monotherapy will lead to an expansion of patient enrollment and discussion with the FDA regarding potential registration strategy in this patient population. The rituximab combination treatment arm of the Phase 2 trial is intended to inform the design of a confirmatory, randomized trial of CUDC-907 in combination with rituximab as compared to rituximab in combination with standard of care chemotherapy.

"We are pleased to report promising clinical activity of CUDC-907 in patients with DLBCL, particularly those with tumors that harbor MYC alterations," said Ali Fattaey, Ph.D., Curis’ President and Chief Executive Officer. "These clinical results are consistent with our preclinical observations where CUDC-907 has a rapid and dramatic effect on MYC protein levels and provides significant anti-tumor activity in in vivo models. We are thankful to our patients for their participation in the Phase 1 clinical trial and, based on these data, we expect the start of a Phase 2 trial that will exclusively enroll patients with relapsed/ refractory DLBCL known to have MYC alterations based on pre-specified selection criteria."

The Phase 1 dose escalation and expansion trial was designed to determine the maximum tolerated dose (MTD), recommended Phase 2 dose and preliminary anti-cancer activity of oral CUDC-907 in patients with relapsed/refractory lymphoma or multiple myeloma (MM). At the time of data cut-off for the ASH (Free ASH Whitepaper) presentation, a total of 72 patients had been enrolled in the trial, including 25 with RR-DLBCL. In the completed dose escalation phase, patients received CUDC-907 daily (QD, doses: 30 or 60 mg), or intermittently on twice weekly (BIW) or thrice weekly (TIW) schedules (doses: 60, 90, 120 or 150 mg) or on a 5 days on, 2 days off (5/2) schedule (dose: 60 mg). CUDC-907 dosed at 60 mg on the 5/2 schedule was determined to be the recommended Phase 2 dose (RP2D). The expansion phase of the trial is ongoing to assess the safety and tolerability of CUDC-907 at the RP2D of 60 mg 5/2 with or without the standard dose of rituximab.

The most common drug related adverse events (AEs) reported in the study have been low grade (Grade 1 and 2) diarrhea, fatigue and nausea. Dose limiting toxicities (DLTs) have consisted of diarrhea and hyperglycemia, and occurred on the QD, BIW and TIW schedules. No DLT occurred at the RP2D of 60 mg 5/2. Other drug-related Grade 3 or 4 AEs reported in 3 or more patients included thrombocytopenia and neutrophil decrease (hematologic AEs) as well as diarrhea, hyperglycemia and fatigue (non-hematologic AEs).

Out of the 25 patients with RR-DLBCL included in the ASH (Free ASH Whitepaper) presentation, 18 were evaluable for response assessment per protocol at the time of data cut-off. The best responses observed in patients with RR-DLBCL were CR (3 patients), PR (5 patients) stable disease or SD (4 patients) and progressive disease or PD (6 patients). A post hoc analysis of pathology reports and/or tumor samples collected showed that 5 of the 8 patients with objective responses had tumors with alterations in MYC oncogene. MYC alterations in the tumor tissue were determined by established criteria used to identify either MYC gene aberrations (copy number gains or translocations) by fluorescent in situ hybridization (FISH) or MYC protein expression by immunohistochemistry (IHC).

About CUDC-907:

CUDC-907 is an oral, dual inhibitor of Class I and II HDAC, as well as Class I PI3K enzymes. Specifically, CUDC-907 is designed to inhibit HDACs 1, 2, 3, 6 and 10 and PI3K-alpha, delta and beta isoforms. CUDC-907 is currently undergoing investigation in a Phase 1 trial to assess its safety, pharmacokinetics and preliminary anti-cancer activity in patients with relapsed/refractory lymphomas and multiple myeloma. CUDC-907 is also being investigated in a separate Phase 1 trial in patients with advanced solid tumors including those with hormone receptor positive breast cancer or with NUT midline carcinoma. The development of CUDC-907 has been supported in part by The Leukemia & Lymphoma Society (LLS) under a funding agreement established in 2011 between Curis and LLS’s Therapy Acceleration Program. For additional details of CUDC-907’s Phase 1 studies, please refer to www.clinicaltrials.gov (study identifiers: NCT01742988 and NCT02307240).

On December 6, 2015 Agios Pharmaceuticals, Inc. (Nasdaq:AGIO), a leader in the fields of cancer metabolism and rare genetic metabolic disorders, reported new data from the dose-escalation phase and expansion cohorts from the ongoing Phase 1/2 study evaluating single agent AG-221, a first-in-class, oral, selective, potent inhibitor of mutant isocitrate dehydrogenase-2 (IDH2), in advanced hematologic malignancies (Press release, Agios Pharmaceuticals, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120425 [SID:1234508423]). The data are being presented at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) taking place December 5-8, 2015 in Orlando. AG-221 is being developed in collaboration with Celgene.

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Data as of September 1, 2015 from 209 patients with IDH2 mutant positive advanced hematologic malignancies treated with single agent AG-221 showed durable clinical activity and a favorable safety profile. More than 50 patients were added as of the last analysis, and 66 patients remain on treatment. In patients with relapsed or refractory AML, the study had an overall response rate of 37 percent (59 of 159 response-evaluable patients) and a complete remission rate of 18 percent (29 of 159 response-evaluable patients). Responding relapsed or refractory AML patients were on study treatment for up to 18 months with a 6.9-month median response duration (not reported at previous data presentations). The overall safety profile observed was consistent with previously reported data.

"With data from more than 200 patients, it is clear that single agent AG-221 has a favorable safety profile and durable response rate in IDH2 mutant hematologic malignancies," said Eytan Stein, M.D., lead investigator and attending physician in the leukemia service at Memorial Sloan Kettering Cancer Center. "In addition, a subset of patients with stable disease had improvements in neutrophil and platelet counts, which may have important clinical implications for reductions in infections and bleeding. We look forward to developing these data further to describe the overall clinical profile for AG-221 in patients with advanced cancers."

"The consistency of the overall response rate and complete remission rate in this study over time is encouraging," said Chris Bowden, M.D., chief medical officer of Agios. "We continue to believe that AG-221 can make a meaningful difference for patients with IDH2 mutant positive cancers and are focused on executing our strategy of speed and breadth with our partner Celgene. We are making rapid progress in the relapsed/refractory and frontline AML settings, with the Phase 3 IDHENTIFY study open for enrollment and plans to initiate the first of two frontline combination studies by the end of the year."

About the Ongoing Phase 1/2 Trial for AG-221 in Advanced Hematologic Malignancies

AG-221 is currently being evaluated in an ongoing Phase 1/2 trial that includes a dose-escalation phase and five expansion cohorts. The first four expansion cohorts have completed enrollment.

Arm 1: 25 patients with IDH2 mutant positive relapsed or refractory AML age ≥60 years, or any patient with AML regardless of age who has relapsed following a bone marrow transplant (BMT)

Arm 2: 25 patients with IDH2 mutant positive relapsed or refractory AML age <60 years, excluding patients with AML who have relapsed following a BMT

Arm 3: 25 patients with IDH2 mutant positive untreated AML age ≥60 years who decline standard of care chemotherapy
Arm 4: 25 patients with IDH2 mutant positive advanced hematologic malignancies not eligible for arms 1 to 3

Arm 5: The Phase 2 portion of the trial includes 125 patients with IDH2 mutant positive AML who are in second or later relapse, refractory to second-line induction or reinduction treatment, or have relapsed after allogeneic transplantation

Data reported here are from patients receiving AG-221 administered from 50 mg to 650 mg total daily doses in the dose escalation arm and 100 mg once daily in the first four expansion arms, as of September 1, 2015. The median age of these patients is 69 (ranging from 19-100). Patients with relapsed or refractory AML received a median of two prior lines of therapy (ranging from one to six). These new data reflect responses in the evaluable population, which include all patients with a day 28 or later response assessment or discontinued before assessment.

Safety Data

A safety analysis was conducted for all 231 treated patients.

The majority of adverse events reported by investigators were mild to moderate, with the most common being nausea, diarrhea, fatigue and febrile neutropenia.

The serious adverse events (SAE) were mainly disease related. Twenty-three percent of patients had treatment-related SAEs, notably differentiation syndrome (4 percent), leukocytosis (4 percent) and nausea (2 percent). Drug-related Grade 5 SAEs include atrial flutter (one patient), cardiac tamponade (one patient), pericardial effusion (one patient) and respiratory failure (one patient).
A maximum tolerated dose (MTD) has not been reached.

Efficacy Data

Seventy-nine out of 209 total response-evaluable patients achieved investigator-assessed objective responses for an overall response rate of 38 percent.

Of the 79 patients who achieved an objective response, there were 37 (18 percent) complete remissions (CR), three CRs with incomplete platelet recovery (CRp), 14 marrow CRs (mCR), three CRs with incomplete hematologic recovery (CRi) and 22 partial remissions (PR).

Of the 159 patients with relapsed or refractory AML, 59 (37 percent) achieved an objective response, including 29 (18 percent) CRs, one CRp, nine mCRs, three CRis and 17 PRs.

Of the 24 patients with AML who declined standard of care chemotherapy, 10 achieved an objective response, including four CRs, one CRp, one mCR and four PRs.

Of the 14 patients with myelodysplastic syndrome (MDS), seven achieved an objective response, including three CRs, one CRp and three mCRs.

Responding relapsed or refractory AML patients were on study treatment for up to 18 months with a median duration of treatment of 6.8 months (ranging from 1.8 to 18 months).

Responses were durable, with a median response duration of 6.9 months in patients with relapsed or refractory AML.
Neutrophil and platelet improvements were observed in some patients with stable disease.
2015 Milestones for AG-221 in Hematologic Malignancies

Remaining milestones for AG-221 in 2015 include:

Enroll patients in the Phase 3 IDHENTIFY study of AG-221, an international, multi-center, open-label, randomized clinical trial designed to compare the efficacy and safety of AG-221 versus conventional care regimens in patients age ≥60 with IDH2 mutant-positive AML that is refractory to or relapsed after second- or third-line therapy. This study is being conducted by Celgene.
Continue to enroll patients into the Phase 2 portion of 125 patients with IDH2 mutant-positive AML who are in second or later relapse, refractory to second-line induction or re-induction treatment, or have relapsed after allogeneic transplantation.
Initiate a Phase 1b combination study of either AG-221 or AG-120 with standard induction (7+3, Ara-C and idarubicin/daunorubicin) and consolidation (Ara-C, or mitoxantrone with etoposide) chemotherapy in newly diagnosed AML patients eligible for intensive chemotherapy by the end of 2015.

Investor Event and Webcast Information

Agios will host an investor event on Monday, December 7, 2015 beginning at 12:00 p.m. ET in Orlando to review data presented at ASH (Free ASH Whitepaper), including new data from the ongoing studies of AG-221 and AG-120. The event will be webcast live and can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.agios.com.

About Acute Myelogenous Leukemia (AML)

AML, a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults. Undifferentiated blast cells proliferate in the bone marrow rather than mature into normal blood cells. AML incidence significantly increases with age, and according to the American Cancer Society, the median age of onset is 66. Less than 10 percent of U.S. AML patients are eligible for bone marrow transplant and the vast majority of patients do not respond to chemotherapy and progress to relapsed/refractory AML. The five-year survival rate for AML is approximately 20 to 25 percent. IDH1 and IDH2 mutations are present in about 15 to 23 percent of AML cases.

About Myelodysplastic Syndrome (MDS)

MDS comprises a diverse group of bone marrow disorders in which immature blood cells in the bone marrow do not mature or become healthy blood cells. The National Cancer Institute estimates that more than 10,000 people are diagnosed with MDS in the U.S. each year. Failure of the bone marrow to produce mature healthy cells is a gradual process, and reduced blood cell and/or reduced platelet counts may be accompanied by the loss of the body’s ability to fight infections and control bleeding. For roughly 30 percent of the patients diagnosed with MDS, this bone marrow failure will progress to AML. Chemotherapy and supportive blood products are used to treat MDS.

On December 07, 2015 MorphoSys AG (FSE: MOR; Prime Standard Segment, TecDAX; OTC: MPSYY) reported that it has published safety and efficacy data on its proprietary drug candidate MOR202, a fully human HuCAL antibody targeting CD38, a highly expressed and validated target in multiple myeloma (MM) (Press release, MorphoSys, DEC 6, 2015, View Source [SID:1234508443]). The data are from a phase 1/2a clinical study in 52 heavily pretreated patients with relapsed/refractory multiple myeloma. The data, which were presented on Sunday, December 6, 2015, at the 2015 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper), show that MOR202 was safe and well tolerated with a 2-hour infusion time. The incidence of infusion-related reactions (IRR) was very low and mainly limited to the first infusion. In this heavily pre-treated patient population, MOR202 demonstrated encouraging responses with a best-in-class tolerability profile.

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"We are very pleased with the updated clinical results for MOR202. The clinically relevant dose regimens show encouraging clinical efficacy combined with a very good safety profile," commented Dr. Arndt Schottelius, Chief Development Officer of MorphoSys AG. "The clinical study will continue as planned, focusing on combination cohorts, as we see the highest potential for MOR202 in combination therapy."

The ongoing phase 1/2a, open-label, multi-center, dose-escalation study is being conducted in several centers in Germany and Austria. The study is evaluating the safety and preliminary efficacy of MOR202 as monotherapy and in combination with the immunomodulatory drugs (IMiDs) pomalidomide (POM) and lenalidomide (LEN) plus dexamethasone (Dex) in patients with relapsed/refractory multiple myeloma. The primary endpoints of the trial are the safety, tolerability and recommended dose of MOR202 alone and in combination with the IMiDs. Secondary outcome measures are pharmacokinetics and preliminary efficacy based on overall response rate, duration of response, time-to-progression, and progression-free survival.

The data presented at ASH (Free ASH Whitepaper) show that MOR202 can be safely administered as a 2-hour infusion and is well tolerated. Infusion-related reactions occurred in only 1 patient (6%) in the cohorts treated with the clinically relevant dose regimens. Patients received a median of 4 prior therapies. The maximum tolerated dose (MTD) has not been reached. In the monotherapy group, comprising patients treated with the clinically relevant dose regimens, 3 out of 9 patients (33%) achieved an objective response rate, with the other 6 patients showing stable disease. In the early combination cohorts at 8 mg/kg MOR202 with IMiDs (n=6), 1 very good partial response (VGPR; to be confirmed in next response assessment), 2 partial responses (PR) and 1 minimal response (MR) were reported. In upcoming cohorts, patients will receive 16 mg/kg MOR202 in combination with pomalidomide (POM) and lenalidomide (LEN) plus dexamethasone. In addition, confirmatory cohorts are planned to validate the recommended dose of MOR202 as monotherapy and in combination with POM/Dex and LEN/Dex.

MorphoSys also presented promising preclinical data demonstrating synergy of MOR202 in combination with different compounds representative of drug classes commonly used in the treatment of multiple myeloma. Another set of pre-clinical data focused on MOR202’s ability to kill targeted cells via ADCC. While MOR202 showed a level of killing of multiple myeloma cells equivalent to that of surrogates of daratumumab and isatuximab, it exhibited significantly reduced killing of NK cells. These results suggest that MOR202 may show a more durable clinical response than other compounds of its class, by sparing the NK cells needed for ADCC.

MorphoSys will hold today, December 7, 2015, at 8:00pm EST (December 8, 2015: 1:00am GMT, 2:00am MEZ) an Investor & Analyst Event at the 2015 ASH (Free ASH Whitepaper) Annual Meeting. Two KOLs will present the new clinical data for MOR208 and MOR202.

On December 6, 2015 bluebird bio, Inc. (NASDAQ:BLUE), a clinical-stage company committed to developing potentially transformative gene therapies for severe genetic diseases and T cell-based immunotherapies for cancer, reported that pre-clinical data from its anti-BCMA oncology program were presented by bluebird bio scientists at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Press release, bluebird bio, DEC 6, 2015, View Source;p=RssLanding&cat=news&id=2120416 [SID:1234508424]).

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"We believe the unique science and translational gene therapy platforms we have built differentiate bluebird bio in the oncology field and have the potential to yield important new therapies for patients living with cancer. Our three oncology posters at ASH (Free ASH Whitepaper) this year, covering critical basic research, translational and manufacturing aspects of our T cell oncology pipeline, demonstrate the strength of our T cell immunotherapy translational science," said Rob Ross, M.D., head of oncology, bluebird bio. "We are also excited to see the first anti-BCMA clinical data from Dr. Jim Kochenderfer of the National Cancer Institute, which was highlighted in yesterday’s press release from ASH (Free ASH Whitepaper). We believe these data provide excellent proof of concept for bb2121 and are pleased that Jim will serve as one of the principal investigators for our Phase 1 study of bb2121."

Abstract #1893: Manufacturing an Enhanced CAR T Cell Product by Inhibition of the PI3K/Akt Pathway During T Cell Expansion Results in Improved In Vivo Efficacy of Anti-BCMA CAR T Cells

Overview and results, presented by Molly Perkins, D.Phil., bluebird bio, include:

bluebird bio explored the potential for culture modifications to improve the therapeutic potential of CAR T cells without adding complexity to manufacturing. The company tested this hypothesis using CAR T cells specific to B cell maturation antigen (BCMA) manufactured using standard IL-2 culture with an inhibitor of PI3K added to the media, or with IL-7 and IL-15, in place of IL-2.
In an in vivo aggressive lymphoma model, mice treated with anti-BCMA CAR T cells cultured only with IL-2 experienced no effect on tumor growth and succumbed to the tumors within two weeks after treatment; anti-BCMA CAR T cells grown in IL-7 and IL-15 also did not affect tumor growth. In contrast, mice treated with anti-BCMA CAR T cells cultured with IL-2 and an inhibitor of PI3K experienced complete and long-term tumor regression.

In an in vivo multiple myeloma model, mice received a single administration of anti-BCMA CAR T cells cultured under various conditions; all treatment groups demonstrated tumor regression regardless of culture conditions. In a model of tumor relapse, two weeks after tumor clearance, surviving mice were re-challenged with the same multiple myeloma tumors on the opposite flank; only animals that had been treated with anti-BCMA CAR T cells cultured with the PI3K inhibitor were able to resist subsequent tumor challenge.

These data suggest that inhibition of PI3K during ex vivo expansion may generate a superior anti-BCMA CAR T cell product for clinical use; this approach could potentially apply to the manufacture of CAR T cell therapies against other oncology targets.
Abstract #3094: A Novel and Highly Potent CAR T Cell Drug Product for Treatment of BCMA-Expressing Hematological Malignancies

Overview and results, presented by Alena Chekmasova, Ph.D., bluebird bio, include:

bluebird bio has developed a CAR targeting BCMA (bb2121) that consists of an extracellular single chain variable fragment scFv antigen recognition domain derived from antibodies to BCMA linked to CD137 (4-1BB) co-stimulatory and CD3zeta chain signaling domains.

Based on receptor density quantification, bb2121 can recognize tumor cells expressing less than 1,000 BCMA molecules per cell.
In a preclinical BCMA+ multiple myeloma xenograft model, a single IV administration of bb2121 anti-BCMA CAR T cells resulted in rapid and sustained elimination of the tumors with 100 percent survival, while a month-long course of anti-myeloma therapy Velcade (bortezomib) only delayed tumor growth.

Using flow cytometry and immunohistochemistry, bb2121 T cells were shown to rapidly target and infiltrate tumors, and T cell expansion was correlated with tumor regression.

bb2121 anti-BCMA CAR T cells also induced xenograft regression and enhanced survival in a preclinical model of advanced Burkitt’s lymphoma.

Taken together, these studies support the potential clinical application of bb2121 for the treatment of patients with tumors expressing BCMA.

Abstract #3243: Characterization of Lentiviral Vector Derived Anti-BCMA CAR T Cells Reveals Key Parameters for Robust Manufacturing of Cell-Based Gene Therapies for Multiple Myeloma

Overview and results, presented by Graham W.J. Lilley, M.Sc., bluebird bio, include:

Successful personalized medicine will require robust and reproducible drug product manufacturing. A series of experiments were conducted to determine whether variations in anti-BCMA CAR surface expression resulted in changes in the activity of CAR T cells.
T cells transduced with varying amounts of virus to yield different amounts of CAR surface expression were diluted with donor-matched untransduced cells to achieve a uniform population of T cells containing 26 ± 4 percent anti-BCMA CAR T cells. When exposed to tumor, these CAR T cell populations exhibited no difference in cytotoxicity against BCMA-expressing cells.

All T cell productions easily achieved a level of anti-BCMA CAR expression that resulted in potent anti-BCMA activity, thus potency of the final drug product was shown to be independent of total anti-BCMA CAR expression on the cell surface.

These data show that the bluebird bio T cell manufacturing process has the potential to overcome significant challenges associated with personalized medicine by reducing the effects of variability while maintaining potency in autologous cellular drug product manufacturing.