NK cell therapy for the treatment of multiple myeloma

At the 2020 Controversies in Multiple Myeloma (COMy) Online Meeting, Michael O’Dwyer, University of Galway, IE, outlined the role of cellular therapies in the treatment of multiple myeloma (MM). Here, we provide an overview, and discuss the status of cellular therapies in the MM setting and promising emerging data surrounding a novel CD38 knockout (CD38^KO) natural killer (NK) cell therapy.¹

Background

Unlike T cells, NK cells do not require prior sensitization to recognize and mount a response against malignant cells. NK cells are, however, dysfunctional in MM, which promotes tumor immune evasion. An increase in inhibitory checkpoint receptors on NK cells and respective ligands on MM cells and regulatory immune cells of the microenvironment is observed in the progression from monoclonal gammopathy of undetermined significance to MM. Subsequently, there is a loss of function of NK cells in patients with MM. The question is, then, could NK cell functionality reinstating be a viable approach in the treatment of MM?

CAR T vs engineered NK cells

Chimeric antigen receptor (CAR) T-cell-based treatments have demonstrated modest success in the treatment of MM. Unfortunately, long-term follow-ups have revealed that B-cell maturation antigen (BCMA)-targeting CAR T-cells demonstrate poor durability in patients with MM. Additional limitations associated with CAR T-cell therapy were outlined by Michael O’Dwyer:

• Collection of autologous T cells from patients that have received intensive therapy can be challenging due to the following reasons:
  • Unable to manufacture T cells in a timely manner
  • Some patients do not receive their CAR T-cell therapy as a result
  • Allogenic collection requires extensive gene editing to prevent graft-versus-host disease (GvHD)
• Antigen loss or down regulation on MM cells can result in resistance to treatment
• Severe cytokine release syndrome (CRS) and neurotoxicity have been associated with CAR T-cell therapies

NK cell immunotherapy has been suggested as an alternative, or complimentary, approach to MM. NK cell therapy has already demonstrated promising results in patients with non-Hodgkin Lymphoma and chronic lymphocytic leukemia, and the nature of NK-cell collection and manufacture allows for an ‘off-the-shelf’ type therapeutic, all the while appearing safe and tolerable (Table 1).

Table 1. General comparison of CAR T-cell and NK cell-based therapeutics by Michael O’Dwyer¹

CAR, chimeric antigen receptor; CRS, cytokine release syndrome; HLA, human leukocyte antigen; ICU, intensive care unit; NK, natural killer
	CAR T-cell therapy	Engineered NK cell therapy
Cell source	Autologous	Allogeneic
Mode of action	Antigen / CAR-dependent	Innate Independent of antigens and HLA molecules
Toxicity	Severe CRS (~30%) Severe neurotoxicity (45%)	No observed CRS or neurotoxicity
Dosing frequency	Single dose	Potential for multidosing
Administration setting	In patient with ICU available	Outpatient

Refining cellular therapy in MM

CD38 has been validated as a target for the treatment of MM, as signified by the widespread approval of daratumumab (dara). However, disease progression still occurs and CD38 remains present on MM cells following relapse to anti-CD38 monoclonal antibodies. Instead, immune exhaustion and lack of functional effector cells have been linked to resistance in these patients. Expression of CD38 by CAR NK cells results in rapid dara-mediated depletion of NK cells, a phenomenon referred to as fratricide. Fratricide not only impacts innate NK cell functionality but also hinders the success of NK cell-based immune therapies. To address this, ongoing preclinical studies are exploring the potential of CD38^KO NK cells.

Ryan Bjordahl and colleagues have developed a multiple-target, adoptive NK cell immunotherapy, FT576, with four important characteristics (Table 2).² Preclinical studies have uncovered that FT576 NK cells are entirely resistant to dara-induced fratricide in vitro and, when combined with dara, demonstrate potent in vivo cytotoxicity in mouse xenograft models. There is also evidence that CD38^KO may enhance NK cell metabolism while providing protection from oxidative stress within the bone marrow microenvironment. As a result, the U.S. Food & Drug Administration has granted investigational new drug status to FT576, and the novel agent will be entering a first-in-human, phase I trial for the treatment of patients with B-cell lymphoma and chronic lymphocytic leukemia in 2020.³

Table 2. Characteristics of the first-in-class NK cell treatment, FT576²

ADCC, antibody-dependent cellular cytotoxicity; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; Il-15, interleukin-15; KO, knockout; mAbs, monoclonal antibodies; MM, multiple myeloma; NK, natural killer
Engineered characteristic	Function
Anti-BCMA CAR	Direct targeting of MM cells
High affinity non-cleavable CD16	Enhance ADCC in combination with anti-CD38 mAbs
CD38KO	Resistance to dara-induced fratricide
IL-15/IL-15 receptor α fusion protein	enhanced NK cell persistence

Further considerations

There were a number of additional influencing factors outlined by Michael O’Dwyer at the COMy Meeting. The tolerability of dara in the presence of potent NK cells, for example, is currently unknown, and there remains the possibility of toxic myelosuppression. One avenue being explored is the use of lower affinity anti-CD38 agents, which solely target MM cells with abnormally high CD38 expression.

Additionally, adoptive NK cells must be able to traffic to the bone marrow; facilitated by adhesion molecules and cytokine receptors, particularly CXCR4, on induced NK cells. Levy et al., showed that NK cells expressing a mutated form of constitutively active CXCR4, migrate more effectively to the bone marrow in murine models.⁴

The above considerations are being continually investigated to optimize the potential of NK cellular therapy.

Concluding remarks

Multitargeted approaches involving NK cells stand as a prospective treatment for MM. Such cellular therapies hold the potential to enhance cytotoxicity, overcome immune-suppressive factors, and boost homing to the bone marrow. In combination with existing treatments, such as dara and BCMA-targeted therapies, NK cell therapy promises to further improve patient outcomes and eliminate minimal residual disease.

Michael O’Dwyer concluded with the following statement: “Ultimately, the goal will be to develop safer, more effective, off-the-shelf therapy for MM, with the aim of improving patient outcome”

Further Resources

The full session is currently available via this link [Correct as of June 17, 2020].