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NK cell therapy for the treatment of multiple myeloma

Jun 22, 2020

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 vsengineered NK cells

Chimeric antigen receptor (CAR) T-cell-based treatmentshave 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’Dwyer 1

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 KONK cells.

Ryan Bjordahl and colleagues have developed a multiple-target, adoptive NK cell immunotherapy, FT576, with four important characteristics ( Table 2). 2Preclinical studies have uncovered that FT576 NK cells are entirely resistant to dara-induced fratricide in vitroand, when combined with dara, demonstrate potent in vivocytotoxicity in mouse xenograft models. There is also evidence that CD38 KOmay 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, FT576 2

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

CD38 KO

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].

Phase II study of ex-vivo expanded cord blood NK cells for the treatment of MM

  1. O'Dwyer M. Cellular therapies: NK cells as a model. Paper presentation.  2020 COMy Congress. May 14, 2020. Online.

  2. Bjordahl R, Gaidarova S, Goodridge JP, et al. FT576: A novel multiplexed engineered off-the-shelf natural killer cell immunotherapy for the dual-targeting of CD38 and Bcma for the treatment of multiple myeloma. Blood. 2019;134(Supplement 1):3214. DOI: 10.1182/blood-2019-131373
  3. Goodman A. Preliminary data on multiantigen-targeted CAR NK-cell therapy for B-cell malignancies. The ASCO Post. https://www.ascopost.com/issues/january-25-2020/preliminary-data-on-multiantigen-targeted-car-nk-cell-therapy-for-b-cell-malignancies/. Published Jan 25, 2020. Accessed June 17, 2020.
  4. Levy E, Reger R, Segerberg F, et al. Enhanced bone marrow homing of natural killer cells following mRNA transfection with gain-of-function variant CXCR4 R334X. Front Immunol.2019;10:1262. DOI: 10.3389/fimmu.2019.01262