PRISMM merges ideas from other trials you may already be familiar with: TAPUR, MATCH and the Metastatic Breast Cancer Project (MBCP). Like TAPUR and MATCH, we aim to measure how tumors with a specific mutation respond to a targeted medication. Like MBCP, we are reaching out through social media to identify patients and expand the pool of clinical trial participants into the community.

Community physicians face challenges in treating patients as cancer progresses and options become limited. Getting insurance to cover off-label medication use can be frustrating, even when a patient has a mutation that has responded in other tumor types. Newer drugs are offered only through clinical trials, which require living near a trial site. And for those patients who do have access to tertiary cancer centers, enrollment can disrupt the important longitudinal relationship with a trusted local oncologist.

This means most patients with advanced cancers seek treatment in the community, so valuable information about tumor, therapy and response is lost to science. This is particularly troubling for rare mutations, because an adequate population can’t be found for study.

With its online recruitment strategy and observational structure, PRISMM aims to circumvent some of these problems. The study is registered at clinicaltrails.gov, NCT04447651.

Spliceosome mutations occur in a variety of cancers. The spliceosome is an intracellular machine that cuts processes (or splices) pre-messenger ribonucleic acids (pre-mRNA) to mature messenger RNA (mRNA). A single gene can be spliced in various ways, leading to variable protein activity.

Genetic mutations in the spliceosome cluster in “hotspot” regions. The most common involves SF3B1, which encodes a protein that appears to be important in correct spliceosome function. These mutations are found fairly commonly in MDS and CLL [1, 2]; they have also been observed less commonly in solid tumors, e.g., 19% in uveal melanoma, and 4% in breast and pancreatic cancers [1].

We and others have shown that creating an SF3B1 mutation in a cell like results in new mRNA transcripts, and that these transcripts are actually translated into abnormal proteins. [7, 8]. These preliminary data suggest that spliceosome mutations may produce a high number of neoantigens, or new proteins recognizable by the immune system. If true, this carries direct therapeutic consequences. In a landmark Hopkins’ study, Le et al. showed that colon cancers with a high mutational burden demonstrated dramatic responses to anti-PD1 therapy [9]. This has led to an understanding that immune therapy is most effective when some kind of mutational burden produces high numbers of neoantigens.

For this reason, we believe patients with tumors that harbor spliceosome mutations may respond to immune therapy, even if their tumor type or genetic analysis otherwise would not suggest this. We have preliminary evidence that this may prove true: In an analysis of five immunotherapy trials that included gene sequencing, we identified 4/251 patients with spliceosome mutations, all of whom demonstrated at least a partial response to anti-PD1 therapy, one showing a durable remission. We have also observed through our molecular tumor board a patient with a durable response who received anti-PD1 therapy whose tumor harbored a spliceosome mutation and importantly the tumor did not have a high mutational burden.

Once we establish that your patient indeed has the mutation of interest, we will reach out to you to request your participation. If you agree, we will request that you provide limited patient records (i.e. most recent clinic note describing the patient’s therapeutic history, most recent radiology and lab report), as well as a blood sample. The blood will be used to look for the mutational profile in the plasma (so-called plasma tumor DNA) as well as immune cells; the results will be used for investigational purposes only, and will not be considered by the tumor board. We will provide a kit for the blood draw and packaging to send it back to us at no charge.

The Molecular Tumor Board will review your patient’s case and provide recommendations. If the board does recommend immune therapy, you can use this documentation to support a request for insurance coverage or even compassionate use directly from the pharmaceutical company. We do not supply drugs directly, but we can provide the necessary forms for this process.

Once you receive the tumor board’s recommendations, you are under no obligation to follow them, of course. If you agree to participate we will send you very brief survey (3-5 minute) once every 1-3 months inquiring about your patient (response to therapy, change in therapy, etc.).