Promising Preclinical Results for Immunotherapy in Multiple Myeloma

Multiple myeloma (MM) is an incurable clonal plasma cell malignancy and the second most common adult hematologic malignancy, with an incidence of 31,000 cases per year.¹  Although immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies significantly improved outcomes in MM, patients still experience disease relapse and resistance to therapy. This raises the need to develop new drugs that can control and eradicate tumor cells more efficiently and durably.

Immunotherapy is now a growing and promising approach in MM, especially adoptive T cell therapy (such as chimeric antigen receptor T-cell [CAR-T] therapy) and bispecific antibodies, which are showing promising results in relapsed or refractory patients. Earlier CAR-T trials in MM indeed showed impressive response rates. However, these responses lacked durability²  and thus opened the door for improved designs that could induce a sustainable antimyeloma effect.

The potency of antibodies in MM has been demonstrated with monoclonal antibodies (mAbs) targeting different MM-specific antigens (CD38, SLAMF7, and BCMA). Bispecific antibodies are engineered to recognize two distinct molecular targets: one specific to the cancer cell of interest and the other on T cells (mainly CD3). This T-cell engagement will direct them to elicit a cytotoxic response toward the cancer cells. This approach has proven to be clinically effective for the bispecific antibody blinatumomab, which targets CD3 and the protein CD19 in B-cell acute lymphoblastic leukemia.³  Moreover, clinical trials of bispecific antibodies targeting CD38 and BCMA in MM have shown promising interim results.

In a recent article in Nature Cancer by Dr. Lan Wu and colleagues, the authors developed a trispecific antibody with three antigen-binding sites targeting CD3 and CD28 on T cells plus CD38 on myeloma cells. CD28 belongs to a class of proteins called costimulatory receptors, which is a critical mediator of T-cell signaling following T-cell receptor activation and drives its proliferation and survival.

The authors showed that the CD28-binding domain augmented the trispecific antibody’s activity by creating three versions of the antibody in which different combinations of the three binding domains were mutated. They tested these versions in three MM cell lines and a humanized NOD/SCID/γ(NSG) mouse model, which had human primary CD8⁺ T cells, inoculated with the NCI-H929 human myeloma cell line. The results of both in vitro and in vivo experiments proved that a functional CD28-targeting domain boosted the T-cell activity above that observed using antibodies lacking it.

The authors also reported that the trispecific antibody stimulates T_H1 function and CD8 memory T cells, which are known to enhance antitumor immunity. They also argued that CD28 expression on myeloma cells could improve antibody affinity and T cell recognition and lysis. Previous studies reported that CD28 is detected on primary myeloma cells in approximately one-third of newly diagnosed patients and increases in frequency during myeloma progression and extramedullary disease.⁴  Indeed, the sensitivity of the CD28 knockout cells to T-cell cytolysis was reduced tenfold to 100-fold.

One of the questions yet to be answered is the risk of cytokine release syndrome with this trispecific antibody in clinical trials. Cytokine release syndrome could occur after excessive stimulation of T cells and can lead to multiorgan failure. In 2006, six healthy volunteers who received a single dose of a CD28 superagonist mAb became critically ill with immune-related toxicities.⁵  Dr. Wu and colleagues argue that they included a monovalent CD28 superagonist that reduced nonspecific cytokine release seen with the CD28 mAb. They have also tested the toxicity profile in non-human primates and observed that gradual exposure through subcutaneous injection induced less cytokine-related toxicities compared to the intravenous route.