General MM,   Relapsed/refractory patients

2017 ASCO Annual Meeting: BCMA is a promising target for directed treatment of MM

The Multiple Myeloma Hub were delighted to attend the 2017 ASCO Annual Meeting held in Chicago, Illinois from June 2nd to 6th. Several poster abstracts and one oral session shared a common theme, in which therapies were designed to target B cell maturation antigen (BCMA) for the treatment of Multiple Myeloma (MM). BCMA is expressed exclusively by plasma B cells and is therefore an ideal candidate for targeted therapy in which the patient’s own immune system is harnessed to kill the tumor cells. Two abstracts focused on patient studies using chimeric antigen receptor engineered T cell (CAR-T) therapies and two studies reported the development of bi-specific antibodies targeting BCMA.

CAR T-Cell Studies

In both a poster presentation and oral discussion session, Jesus G. Berdeja from the Sarah Cannon Research Institute, Nashville, Tennesse, revealed preliminary data from an ongoing phase I study of a second-generation CAR T-cell modality targeting BCMA (bb2121), generated by bluebirdbio in collaboration with Celgene (Abstract 3010). The trial has enrolled heavily pre-treated relapsed and refractory MM patients who had received ≥ 3 prior regimens (with an overall median of 6), including a proteasome inhibitor and an immunomodulatory agent, or who are double-refractory, and have ≥ 50% BCMA expression on plasma cells.

Key Highlights:
  • Following collection of PBMC’s, patients (pts) underwent lympho-depletion with Flu (30 mg/m2) / Cy (300 mg/m2) daily for 3 days then received 1 infusion of bb2121
  • Planned dose escalation of 5, 15, 45, 80 and 120 x 107 CAR+ T cells was used
  • By November 18th 2016, 11 patients (pts) had received bb2121 in the first 4 doses, and 9 patients had reached at least 1 month of follow-up
  • No grade 3 AEs or higher were reported
  • Most common AEs were grade 1: neutropenia (89%), leukopenia (67%), anemia (44%)
  • Grade 1-2 CRS = 73% (8/11), but was treatable
  • All pts treated with doses of 15 x 107 or higher remained in the study
  • Overall response rate (ORR) = 78% (including 2 sCRs and 2 MRD-negative responses (1 sC, 1 VGPR))
  • CAR+ T cell expansion was consistently observed

This preliminary trial with the bb2121 CAR T-cell modality gave highly promising results, at dose levels higher than 5 x 107 CAR+ T cells. The ongoing trial of bb2121 is recruiting 50 more patients within the US.

In a late breaking abstract (Abstract LBA3001), a second CAR T-cell study was presented by Wanhong Zhao an associate director of hematology at The Second Affiliated Hospital of Xi’an Jiaotong University in Xi’an, China. Wanhong Zhao described a single arm phase I clinical trial treating MM using a CAR-T modality designated LCAR-B38M CAR-T, developed by Nanjing Legend Pharma, and which principally targets BCMA.

Key Highlights:
  • Total of 19 patients (pts) with RRMM were enrolled and treated before January 2017
  • Pts were followed for a minimum of 4 months
  • Median number of infused cells = 4.7 (0.6 ~ 7.0) × 10e6/ kg in 3 doses over a week
  • Stringent CR = 14, PR = 1, VGPR = 4
  • 5 pts followed for 12-14 months; all 5 remain in sCR status
  • Stringent complete response (sCR) = 14 pts; PR = 1 pt; VGPR = 4 pts
  • One incidence of disease progression from VgPR
  • Most common adverse event (AE): cytokine release syndrome (CRS) = 74% (14 pts), but was “transient, mild and manageable”
  • Grade 1 CRS = 9 pts; Grade 2 CRS = 2 pts, Grade ≥3 CRS = 2 pts, but both recovered quickly
  • Overall Response Rate (ORR) = 100%
  • Since the preliminary assessment, 26 more pts were enrolled
  • Clinical remission has been observed in 94% (33/35 pts)

In Dr. Zhao’s talk, he illustrated very visible signs of remission using specific patients with highly advanced disease. One patient had widespread extramedullary lesions visible all over his body. Following 18 days of treatment with LCAR-B38M these lesions were markedly reduced, and had cleared almost completely by day 83. Eight weeks of CAR T therapy also led to a massive decrease in a large extramedullary lesion next to the thoracic vertebrae for another isolated patient. The typical progression of a patient throughout therapy was shown, with most patients progressing through from partial response (PR) to very good partial response (VgPR) and finally to stringent complete response (sCR) by 7 weeks, although efficacy was observed as early as 10 days into the treatment regimen. Future trials of LCAR-B38M are expected to enrol 100 more RRMM patients in China, and a second US trial is planned for 2018.

The responses with both CAR T’s appear to durable, with high levels of remission leading to whisperings amongst the MM community that there could finally be a cure on the horizon.

Bi-specific Antibody Studies

The development of bi-specific antibodies designed to target plasma cells with one arm and to recruit T-cells with another, termed BITEs (Bi-specific T-cell engaging antibodies), are the basis of several innovative MM therapies. In a poster discussion session, Ben Buelow from Teneobio, Inc. USA, outlined the development of a fully humanized bi-specific antibody which targets BCMA as the B-cell specific antigen, and uses a CD3-binding arm to recruit T cells (Abstract 8017).

 Key Highlights:
  • UniRats were immunized with CD3 or BCMA
  • Antigen-specific antibodies were identified using antibody repertoire sequencing and high-throughput gene assembly, expression, and screening
  • Recombinant proteins and cells were used to select high affinity binding VH sequences
  • In-vitro testing for T-cell activation used a cytokine-release assay and tumor cell killing was assessed using calcein-release
  • In-vivo testing was carried out in NSG mice transfused with myeloma cells and human PBMCs
  • BCMA-specific UniAbs bound plasma cells with a high affinity (100-700pM) and cross-reacted with cynomolgus plasma cells
  • T cell agonists were identified that bound human T cells with high and low affinities, and cross-reacted with cynomolgus T cells
  • Bi-specifics with a strong (H929 cytotoxicity: EC50=27pM) arm and a weak T cell activating arm (H929 cytotoxicity: EC50=1170pM) led to T-cell activation and tumor-cell cytotoxicity in-vitro
  • Bi-specifics with a weak CD3 engaging arm seemed to be advantageous as it resulted in low levels of cytokine production, even at doses saturating for cytotoxicity
  • Reduced tumor load and increased survival was observed when bi-specifics were co-administered with human PBMCs, compared to control antibodies

In another poster (Abstract 8045) presented by Thorsten Gantke from Affimed GmbH, Heidelberg, Germany, a novel approach to recruit, and enhance NK-cell toxicity, was described. A highly potent BCMA/CD16A-directed bispecific antibody (designated AFM26), which is tetravalent and engages NK cells with high affinity, has been developed and tested in-vitro using MM cell lines and freshly isolated tumor cells. AFM26was found to binds NK-cells with high avidity: KD: 1-2nM, via a bivalent interaction with CD16A (FcγRIIIa). Prolonged cell surface retention was observed and was unaffected by high levels of polyclonal IgG; binding to CD16 was also unaffected by common receptor polymorphisms. AFM26 selectively induced lysis of MM cells in-vitro, expressing variable degrees of BCMA. Of note, its potency was superior to that of elotuzumab and daratumumab, and importantly it did not drive depletion of NK-cells. This NK-cell directed approach may be advantageous after stem cell transplant, as NK-cells are the first to re-appear.

In conclusion, these two bi-specific antibodies show promising early data in the development and in-vitro testing phase. The Teneobio construct is in a more advanced stage of development and performed well in-vivo using rats; future development of AFM26 from classical antibody formats is necessary. Interestingly, the Tenebio construct indicated that the use of lower affinity T cell engagement could be preferable in MM. However, the real test will be the further development for use in humanized mouse MM models, and ultimately progression into clinical trials. 

 Conclusion:

These four presentations indicate that BCMA is a valid target for both antibody- and cellular- based therapies to treat MM. Despite BCMA being a highly specific marker of plasma cells, researchers have raised concerns regarding the low levels present at the plasma cell surface. However, in light of the data described, these concerns now seem unwarranted. We eagerly await more extensive development and testing of both types of BCMA-directed treatment modalities.

 

References
  1. Jesus G. Berdeja et al. Developmental Therapeutics—Immunotherapy. American Society of Clinical Oncology (ASCO®) Annual Meeting; 2017 June 2–6; Chicago, IL, USA. Abstract 3010.
  2. Frank (Xiaohu) Fan et al. Developmental Therapeutics—Immunotherapy. American Society of Clinical Oncology (ASCO®) Annual Meeting; 2017 June 2–6; Chicago, IL, USA. Abstract LBA3001.
  3. Ben Buelow et al. Hematologic Malignancies—Plasma Cell Dyscrasia; Poster Discussion Session (Board #343). American Society of Clinical Oncology (ASCO®) Annual Meeting; 2017 June 2–6; Chicago, IL, USA. Abstract 8017.
  4. Thorsten Gantke et al. Hematologic Malignancies—Plasma Cell Dyscrasia. American Society of Clinical Oncology (ASCO®) Annual Meeting; 2017 June 2–6; Chicago, IL, USA. Abstract 8045.