Targeting minimal residual disease: a path to cure?

Abstract

Therapeutics that block kinases, transcriptional modifiers, immune checkpoints and other biological vulnerabilities are transforming cancer treatment. As a result, many patients achieve dramatic responses, including complete radiographical or pathological remission, yet retain minimal residual disease (MRD), which results in relapse. New functional approaches can characterize clonal heterogeneity and predict therapeutic sensitivity of MRD at a single-cell level. Preliminary evidence suggests that iterative detection, profiling and targeting of MRD would meaningfully improve outcomes and may even lead to cure.

Figure 1.. Paradigms for management of MRD.

The current approach is to treat patients until they achieve a complete remission (CR). This could be through surgical resection, radiation, chemotherapy or combinations. Patients are then typically observed until they relapse. Instead, minimal residual disease (MRD) could be sampled iteratively, tested for therapeutic susceptibility and treated with the agent(s) identified as most effective by that testing. Once a patient’s MRD falls below the minimum detectable threshold (dashed line), treatment could either be stopped, continued indefinitely, or continued for a defined period with curative intent. Potential advantages and disadvantages of targeting MRD are listed and discussed further in the text.

Figure 2.. Current paradigm for management of MRD in patients with acute lymphoblastic leukaemia.

Induction therapy for acute lymphoblastic leukaemia (ALL) induces morphologic remission (<5% blasts, “complete remission”) in most patients. Minimal residual disease (MRD), or small amounts of disease undetectable by standard morphologic review, is often detectable using sensitive MRD-assessment techniques such as flow cytometry and sequencing approaches. The current application of MRD testing is to guide the intensity of consolidation therapy. Patients who achieve undetectable or “low” MRD are assigned to lower intensity therapy. Patients who have “high” levels of MRD are assigned to higher intensity therapy. In each case, the intensity is based on predictions from prior studies of the lowest amount of therapy necessary to eradicate MRD. This probabilistic approach results in undertreatment and overtreatment of some patients. Each panel in the figure illustrates a hypothetical level of MRD in the absence of consolidation therapy (top line) and the same MRD optimally treated with consolidation (bottom line).

Figure 3.. Suspended microchannel resonator (SMR) and workflow for the mass accumulation rate (MAR) assay.

(A). An example of the data collection using the SMR is shown as in Stevens et al. Imatinib was added to cultured BCR-ABL-expressing BaF3 cells at T=0 and the culture was continuously sampled using a serial SMR for 8 hours. Each cell takes ~20 min to pass through the 12 serial SMRs (sSMRs) = 1^st SMR, red = last SMR) and the slope of the resulting growth trajectory is the MAR. Initially, the trajectories have a positive slope, but after 6 hours, the slope approaches zero. Although the imatinib treated cells remained viable for >36 hours before significant induction of apoptosis, the MAR decreases in just a few hours. (B) Functional properties such as MAR that are rapidly affected by effective therapeutics and precede longer-term phenotypes (e.g. loss of viability) can be linked to molecular properties by isolating individual cells in wells and performing downstream assays. In this example, MAR is used to identify responding (sensitive) and nonresponding (resistant) cells prior to sc-RNA-seq in order to search for programs and cell states associated with resistance.