Effective cancer immunotherapy represents a major paradigm shift in the treatment of solid and hematologic malignancies. From the development of monoclonal antibodies (MoAb) to antibody-drug conjugates targeting cancer-associated epitodes until the most recent checkpoint blockade and bioengineered chimeric antigen receptor (CAR) T cells, the natural history of several types of cancer has been radically impacted by these treatments.
Historically, the greatest hurdle in developing a successful immunotherapy in multiple myeloma (MM) has been the presence of a dysfunctional immune system in MM, resulting from both tumor cell and bone marrow (BM) microenvironment factors. Over the last two decades, investigators at Dana-Farber have elucidated the immunosuppressive mechanisms in MM and helped develop methods to overcome immunoparesis, and augment immune function.
Aided by the preclinical and clinical investigation at Dana-Farber, in 2015, the anti-CD38 antibody, daratumumab, became the first MoAb to receive FDA approval for treatment of MM. Shortly afterwards, elotuzumab, an anti-SLAMF7 MoAb, was also FDA approved for treatment of MM in combination with lenalidomide and dexamethasone (Rd). These agents have provided a proof of principle that MM can be effectively targeted by immunotherapies.
Current research efforts at the Jerome Lipper Multiple Myeloma Center at Dana-Farber are focused on three major areas in immunotherapy: antibody-drug conjugates; enhancement of T-cell mediated anti-MM cytotoxicity via CAR-T cells, bispecific T cell engagers (BiTEs) and vaccination strategies; and checkpoint blockade. This tripartite immunotherapy approach is summarized in Figure 1 below.
The key for development of effective cellular immunotherapies and MoAbs is the identification of a cancer antigen which is both highly expressed on the cancer cell surface and (ideally) necessary for cancer cell survival, so as to limit the development of resistance secondary to target-antigen downregulation. Furthermore, it is preferential, but not necessary, for the target antigen to be selectively expressed on cancer cells in order to limit side effects related to targeting normal cells. The BCMA protein has been recently identified by Dana-Farber researchers as a suitable target for immunotherapy in MM, given its uniformly high cell-surface expression in MM patients, its pro-survival function in the context of the TACI/APRIL and NF-κB pathways, as well as lack of expression in most normal tissues.
To increase activity of antibodies targeting such antigens, antibody-drug conjugates have been developed as a strategy to deliver highly cytotoxic chemotherapy selectively to cancer cells. An anti-BCMA MoAb conjugated to the microtubule inhibitor monomethyl auristatin-F (MMAF) is currently being evaluated in a phase 1/2 clinical trial in relapsed/refractory MM (RRMM) with promising initial results in a heavily pre-treated population. A clinical trial of an anti-CD138 MoAb conjugated to the maytansinoid DM4 in combination with Rd or pomalidomide in patients with RRMM has recently completed accrual. Preliminary results also show high response rate.
A phase 1 trial of BCMA CAR-T cells is currently open at our center. Based on laboratory research performed at our center, BCMA BiTEs are also anticipated to enter clinical trials soon as an alternative strategy to direct cellular immunity specifically against MM. Another CAR T cell approach directed at NKG2D has recently completed initial accrual.
Our group has extensively evaluated the role of checkpoint inhibitors as a tool to overcome cancer-tolerant microenvironment in MM. Single agent PD-1 inhibitors have not elicited responses in MM patients, despite expression of PD-L1 on primary MM cells, myeloid-derived suppressor cells (MDSC) and plasmacytoid dendritic cells (pDC); and expression of PD-1 on BM-resident T lymphocytes. The lack of effectiveness of PD-1 blockade suggests that the highly immunosuppressive MM BM microenvironment may limit the activity of some checkpoint inhibitor approaches. To overcome this limitation, we are exploring two different strategies. First, we are combining checkpoint inhibitors and other therapies, such as nivolumab and pembrolizumab, in regimens with Rd, which could harness the immunostimulatory properties of lenalidomide. Second, there is an ongoing research effort to skew the MM BM microenvironment away from cancer-tolerant, immunoparesis toward active, anti-cancer immunosurveillance. In particular, therapies aimed at reducing or altering the immunosuppressive function of pDCs, MDSCs, macrophages, Th17 and Treg T cell subsets are currently being investigated at Dana-Farber. Two such strategies are the NKG2D CAR T cells discussed above and the clinical use of the PD-L1 blocking antibody durvalumab. Increased expression of PD-L1 on MM and other BM microenvironment cells indicates that inhibiting PD-L1 rather than PD-1 may have a more profound effect. Durvalumab alone or in combination with pomalidomide is being evaluated in RRMM.
Finally, vaccination strategies, particularly in the context of low burden disease (smoldering MM (SMM) and/or post autologous stem cell transplant-ASCT), are being investigated. In collaboration with David Avigan, MD, at Beth Israel Deaconess Medical Center, a randomized phase 2, multicenter trial in patients with MM undergoing ASCT is evaluating the impact of a vaccination strategy with a dendritic cell/myeloma fusion plus lenalidomide and GM-CSF, lenalidomide alone, or GM-CSF alone. The primary endpoint is the fraction of patients in CR and/or sCR one-year post ASCT. Peptide vaccine strategies in combination with Rd are also being evaluated in SMM as a tool to stimulate autologous anti-MM immunosurveillance and delay progression to active disease.
In conclusion, this is an exciting era for immunotherapy, and many treatment strategies are effectively altering and/or redirecting the immune system against cancer. Investigators at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute are leading the development of these promising immunologic therapies that may contribute to better outcomes, or potentially even cures, for some patients.
Figure 1. Tripartite Immunotherapy Approach against Multiple Myeloma. The figure summarizes the three major immunotherapy approaches to MM under development at Dana-Farber. In the middle is a MM cell, with the mitotic spindle sprouting from the centromeres and chromosomes aligned along the metaphase plate. In section A, monoclonal antibodies (MoAbs) and antibody drug-conjugates (ADCs) are represented. In green are FDA approved agents, in red investigational ones. Daratumumab (DARA) and SAR650984 (SAR) target CD38; elotuzumab (ELO) targets SLAMF-7 while indatuximab ravtansine (BT062) and J6M0-mcMMAF (J6M0) are ADC targeting CD138 and BCMA, respectively. ELO induces antibody-dependent cell cytotoxicity (ADCC) while DARA and SAR trigger complement dependent cytotoxicity (CDC), ADCC and direct cytotoxicity from crosslinking. Both DM4 and MMAF are released intracellularly upon internalization of ADC-antigen complex. DM4 and MMAF bind to microtubules and inhibit their polymerization, resulting in mitotic arrest and apoptosis. Section B is a representation of multiple strategies to enhance T-cell mediated anti-MM cytotoxicity. From left to right, interaction with MM-DC vaccine or with autologous DC presenting peptides derived from the PVX-140 vaccine elicits a specific T-cell response against MM. A BiTE facilitates direct contact between cytotoxic T cells and BCMA expressing MM cells, thus directing specific, anti-MM cytotoxicity. Finally, CAR T cells against NKG2DL and BCMA are shown. All these strategies result in direct T-cell mediated MM cell lysis.
Rationale for checkpoint blockade in MM is shown in section C. Anergic and/or exhausted cytotoxic T and NK-T cells are represented in shades of green and blue, respectively, while immunosuppressive myeloid derived suppressor cell (MDSC) and plasmacytoid dendritic cell (pDC) are in pink and red, respectively. PD-1 and its ligand PD-L1 are complementary transmembrane proteins expressed on effector and target cells, respectively. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and killer cell immunoglobulin-like receptor (KIR) as potential targets of therapy are also depicted on effector cells.
Around the MM cell are important pathogenic features of the BM microenvironment. In the upper left corner is the imbalanced osteoblast/osteoclast ratio, favoring osteoclastogenesis and bone reabsorption. In the upper right corner is the increased neoangiogenesis, while in the upper middle portion of the cartoon is the tumor-tolerant immune system, characterized by an excess of pDCs, MDSCs, T helper 17 (TH17) and regulatory T (treg) cells with anergic/exhausted T and NK-T cells. Cytokines that are key for MM pathogenesis are represented as orange ovals.
Abbreviations: DKK1: dickkopf WNT signaling pathway inhibitor 1; IL-6: interleukin 6; MIP-1α: macrophage inflammatory protein 1-alpha; IL-17: interleukin 17; IL-3: interleukin 3; RANKL: RANK ligand; VEGF: vascular endothelial growth factor; TGFβ: transforming growth factor beta; TNFα: tumor necrosis factor alpha; IL-1β: interleukin 1β; IL-10: interleukin 10; HGF: hepatocyte growth factor.