Editorial theme | Mechanisms of resistance to immunotherapies

This second article of our editorial theme on ‘escape/resistance to new therapies in multiple myeloma (MM)’ will have a look at the treatment-related mechanisms of disease resistance and how to overcome this challenge, with a special focus on CD38-directed antibody therapies. The first article on the mechanisms of resistance to anti-B-cell maturation antigen (BCMA) can be found here.

The dysfunction of the immune system may lead to disease progression and an increased rate of infection in patients with MM. Currently, several available therapeutic options interact with the immune system in different ways, including monoclonal antibodies, bispecific antibody therapies, immunomodulators, vaccines, and adoptive cellular therapies.¹

During the 7th World Congress on Controversies in Multiple Myeloma (COMy 2021), Niels van de Donk discussed the mechanisms of resistance to immunotherapy in MM¹, and we are pleased to describe key points from his talk to cover this topic. In addition, Franssen and colleagues recently published in the Journal of Clinical Medicine, a review on the resistance mechanisms to CD38-directed antibody therapy.²

Resistance mechanisms

The mechanisms of resistance can be broad (i.e., genetic lesions, clonal heterogeneity, immune cell activity and frequency, and the immunosuppressive bone marrow environment) or resistance may be therapy-specific due to differences in the expression level or mutations in a specific target protein.

Disease-specific mechanisms

Clonal heterogeneity

In MM, multiple subclones coincide, and a specific, resistant subclone may greatly expand during treatment compared with other subclones, leading to resistance. If spatial heterogeneity adds on, resistance may become even more complex. Cell surface markers expressed on subclones may be targeted with immunotherapy; however, clonal evolution may occur as a result of differences in target expression or the expression of complement inhibitors.

Combining immunotherapies with other immunotherapies or traditional treatment options may have potential in this regard. Triplets have been shown to be superior to doublets and monotherapy options to prevent resistance and improve survival.

Another approach may include targeting two myeloma-associated antigens concurrently to prevent antigen escape. Combining a potent anti-CD38 antibody (e.g., daratumumab) with BCMA/GPRC5D T-cell-redirecting bispecific antibody was shown to prevent antigen escape. Dual chimeric antigen receptor (CAR) therapies were also investigated and showed benefit in patient outcomes.

Bone marrow microenvironment

As a component of the bone marrow microenvironment, the presence of stromal cells was associated with the induction of immune resistance to daratumumab both in cell lines and patients, and also less CAR T-cell activity. Stroma cells drive resistance by inducing anti-apoptotic signaling pathways and enabling tumor cells to continue expanding. These findings may provide a basis for further research in inhibiting anti-apoptotic signaling.

Frequency and activity of immune cells

The resistance may also develop when immune cells, including B cells, T cells, and NK cells, are detected in low levels or show no function.

Daratumumab has been shown to eliminate NK cells with high expression of CD38 by promoting fratricide, where NK cells kill each other. In case of no CD38 expression, approaches including an anti-CD38 antibody and adoptive transfer of CD38 knock-out NK cells are currently under investigation in preclinical and clinical studies.¹

The success of CAR T-cell therapies also depends on the quality of T cells harvested and the activity of CAR T-cells given to patients. Some of the strategies under investigation to increase the quality of T cells are: collecting T cells at earlier stages of the disease, avoiding immunosuppressive drugs before leukapheresis, and collecting allogeneic T cells from healthy donors.¹

Immune suppressor cells

A high number of regulatory T cells (Tregs) in the bone marrow has been associated with a reduced response to novel immunotherapies like talquetamab compared with low Tregs. When CD4⁺ CD25⁻ T cells (effector T cells) were added in vitro to Tregs, the lysis of myeloma cells with talquetamab improved and it was significantly higher with CD4⁺ CD25⁻ T cells only. The future direction to explore would be eradicating Tregs with a bispecific antibody before or during therapy, using low-dose cyclophosphamide, or targeting CD38⁺ Tregs with anti-CD38 therapy.¹

Therapy-specific mechanisms

Expression of target proteins¹

Immune modulators show activity by binding cereblon. Not surprisingly, previous studies have shown that immune modulators, lenalidomide and pomalidomide, stopped working in the absence or low levels of cereblon. Moreover, lenalidomide-refractory patients demonstrated low cereblon expression. Iberdomide, a cereblon E3 ligase modulator, has shown enhanced binding to cereblon and greater in vitro immune-stimulatory activity and could potentially be used to treat patients with lenalidomide/pomalidomide-refractory disease.

Baseline CD38 levels play an important role in the response to CD38-directed therapies, and studies have shown that patients with partial response to daratumumab had higher CD38 expression levels. Adding all-trans retinoic acid (ATRA) to daratumumab improved daratumumab-mediated complement-dependent cellular cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). ATRA also has been shown to upregulate CD38 expression on MM cells. Investigators are currently evaluating the agents that would improve CD38 levels in combination with anti-CD38 therapies.

Similar findings on BCMA baseline expression and downregulation have also been described in MM cells derived from BCMA-refractory patients, which we summarized here.

Additional mechanisms described with CD38-targeted agents²

Table 1 summarizes the mechanisms of resistance, and the impact and potential approaches to overcome resistance.

Table 1. A summary of resistance mechanisms to CD38-directed therapy*

Resistance mechanisms to CD38-directed therapies may differ from other MM therapies, highlighting the following:

• Lower expression of complement inhibitory proteins—CD55, CD59—was associated with increased susceptibility to daratumumab-mediated CDC, and patients who experienced disease progression while on daratumumab therapy showed significantly higher CD55 and CD59 expression on bone marrow and circulating MM cells. ATRA has been shown to decrease the CD55 and CD59 expression in ex vivo models.
• Cell adhesion-mediated immune resistance occurs when MM cells in the bone marrow interact with other cells (e.g., bone marrow stromal cells) and become resistant to targeted agents. Studies have shown that this adhesion significantly inhibits daratumumab-mediated ADCC by upregulating the anti-apoptotic protein in MM cells. A small molecule, YM-155, was shown to restore daratumumab-mediated ADCC to some extent.
• Fc-gamma receptor (FcγR) activation on macrophages and NK cells drives ADCC and antibody-dependent cell-mediated phagocytosis (ADCP). FcγR 3A and 2B polymorphisms lead to an impaired activity of these receptors and were associated with a lower response and progression-free survival (PFS) on daratumumab.
• CD47 is significantly upregulated in drug-resistant MM cells, and inhibiting the CD47 and signal regulatory protein α (SIRPα) interaction was shown to increase phagocytosis induced by several therapeutic antibodies. A potential way of eliminating this resistance may be the reduction of CD47 expression on tumor cells by using low-dose cyclophosphamide, which enhances daratumumab-mediated ADCP.
• Immunomodulatory activity also plays a role in resistance to CD38-directed therapy. Daratumumab therapy is associated with an expansion of T cells and T-cell clonality; the lower frequency of activated T cells and effector memory T cells was observed during relapse after daratumumab therapy. The combination of daratumumab and an immunomodulatory drug (IMiD) was associated with a more apparent T-cell activity profile. On the other hand, increased upregulation of the checkpoint inhibitors was seen in patients resistant to daratumumab, suggesting the addition of immune-checkpoint inhibitors may improve treatment responses.

Conclusion

Resistance may occur in many ways in patients with MM, and there are currently several approaches under investigation to overcome resistance to immunotherapy. A better understanding of resistance mechanisms has led to more effective treatment strategies. CD38-directed therapies have changed the treatment landscape in MM, and currently, daratumumab is used in first-line treatment. Thus, it is highly likely that patients will develop daratumumab refractoriness at earlier stages, making it crucial to continue gaining insights into resistance mechanisms to CD38 antibody therapy.