Cancer Immunoprevention: A Case Report Raising the Possibility of “Immuno-interception”

The clinically demonstrated utility of antiviral vaccines to reduce risk of virally initiated cancers represents a major success in cancer immunoprevention. There is interest in the possibility that immunoprevention may also be useful where viral carcinogenesis does not play a major role (1–6).

Therapies that target immune checkpoints lead to impressive clinical improvements in subsets of patients with advanced cancer (7), but the hypothesis that these therapies can be used to reduce cancer risk has not been fully explored.

Muir and colleagues (8) and Torre (9) independently described a syndrome of cutaneous neoplasms associated with increased risk of visceral cancers. This was later recognized as a variant of Lynch syndrome, caused by germline pathogenic variants in mismatch repair genes, resulting in a “mutator phenotype” associated with >12 mutations/10⁶ bases (6, 10).

It is recognized that cancers with a high-mutational burden respond better to immune checkpoint blockade than those with low-mutational burden (11). Therefore, as expected, cancers with mismatch repair deficiency tend to respond well to these treatments (12, 13).

There is an obvious clinical need to reduce cancer incidence in patients with DNA repair deficits, and prophylactic surgery is commonly employed. Clinical trials designed to evaluate strategies to reduce cancer incidence are challenging: in populations where baseline risk is low, a large number of subjects and long follow-up periods are required. On the other hand, studies of interventions for patients with syndromes associated with greatly increased risk are logistically challenging because individual cases are rare and geographically dispersed.

We provide here an “n = 1” case report of a man with Muir–Torre syndrome consistent with the possibility that immune checkpoint blockade is useful for cancer prevention.

Following informed consent, and with anonymization conforming to policies of local institutional review board, we reviewed the entire available medical history of a patient with Muir–Torre syndrome who had received immunotherapy with pembrolizumab for treatment of invasive bladder cancer. Molecular diagnosis was obtained by protein truncation test and sequencing as described below (14).

The patient is a 64-year-old male of Egyptian origin. His mother had a history of multiple neoplasms, but her clinical details are unavailable and genetic testing was not performed. He was first referred to our clinic in 2005, and we were able to obtain detailed medical records dating back to February 1999.

In view of his personal and family history of multiple neoplasms, leukocyte RNA was analyzed for a mutation in the MSH2 and MLH1 genes using the protein truncation test. A truncating germline mutation was identified in Segment 1 of the MSH2 gene. DNA sequencing revealed the presence of a splice site mutation (1661+1G>T). This result was consistent with the clinical presentation that showed features of the Muir–Torre syndrome.

The patient was subsequently followed carefully by dermatology, urology, and gastroenterology consultants. Table 1 provides a list of lesions detected during the period of detailed observation, starting in February 1999 and extending to March 2020. A total of 136 neoplasms, predominately premalignant (or hyperplastic), were detected over the 18-year period (mean 7.4 neoplasms/year, range 2–26, median 12), as shown in Fig. 1. Major surgical procedures included a right colectomy in 1991 for colon polyps and Dukes Stage C colon cancer (carried out at a community hospital before referral to our center), and small bowel resections in 2006, 2009, 2013, as well as 2017 for neoplastic lesions as noted in Table 1. He also had numerous smaller procedures, mainly excision of skin neoplasms and multiple polypectomies.

In November 2017, the patient was found to have invasive papillary urothelial carcinoma involving the right ureterovesical junction as well as Gleason grade 9 prostate cancer. Neoplasia of the genito urinary system has been previously described in Lynch syndrome, but we did not have access to tissue to allow us to determine whether a DNA repair deficit was involved in the pathogenesis of these cancers in our patient. Surgery was considered but was refused by the patient. Therefore, he received a multimodal treatment regimen comprised of chemo–radiotherapy, followed by 1 year of immunotherapy administration with pembrolizumab, 200 mg i.v. every 3 weeks. This was felt to be an optimal treatment program, given that Muir–Torre syndrome is associated with a high-tumor mutational burden, which in turn is associated with high probability of utility of immune checkpoint blockade treatment. Specifically, he received 75 mg/m² of intravenous gemcitabine weekly during radiotherapy, and 60 Gy delivered in 20 fractions to the prostate, 50 Gy delivered in 20 fractions to the bladder, and 40 Gy delivered in 20 fractions to the pelvic nodes. He also received androgen deprivation therapy for the prostate cancer. The patient experienced significant gastrointestinal toxicity related to the chemo–radiation treatments, which was managed symptomatically and resolved prior to the commencement of pembrolizumab treatments in April 2018. The pembrolizumab treatment (200 mg i.v. every 3 weeks) was well-tolerated and continued for 1 year.

During and following the 12 months of immunotherapy, with continuous multidisciplinary surveillance similar or even more intensive to that undertaken since 1999, we noticed an absence of new neoplasms, including both premalignant lesions and cancers. Cystoscopy and imaging carried out in February 2020 confirmed absence of residual urothelial cancer. In view of the risk of autoimmune disease that might be associated with continuous immunotherapy administration for an indefinite period and due to the absence of detectable neoplasia in the patient, it was decided to stop immunotherapy in April 2019.

As of the time of preparation of this article, the unusual period of absence of new epithelial malignancies continued from initiation of pembrolizumab in April 2018 until March 2020, for a total of 22 months without a new diagnosis of cancer or of a premalignant hyperplastic lesion. With respect to his Gleason grade 9 prostate cancer, he remains without detectable disease with a PSA of zero, but this may be attributable in whole or in part to an excellent response to androgen deprivation therapy given simultaneously with immunotherapy. An FDG-PET scan carried out on November 14, 2019 was also normal. This contrasts with the patient's prior history characterized by a mean of 7.5 new neoplasms per year.

This case is consistent with the possibility that immune checkpoint therapy reduces the risk of developing clinically detectable cancers in patients with Lynch syndrome, and possibly in those with other DNA repair deficits. A more convincing demonstration would obviously require longer follow-up, additional molecular, pathologic, and immunologic characterization of lesions observed, and more patients, but such a study would be challenging to execute.

We speculate that checkpoint blockade does not actually block carcinogenesis at the cellular level; it is more likely that it increases the probability that a host immune response will eliminate hyperplastic or neoplastic clones before they become clinically detectable. While pembrolizumab was prescribed for bladder cancer treatment, our patient's history raises the possibility that treatment may have also acted as an immunologic “cancer interception” strategy (15) effectively reducing risk of developing new cancers and new clinically detectable hyperplastic lesions.

A practical issue in the management of this patient and in any other situation where immune checkpoint blockade would be used for cancer prevention concerns the duration of therapy. Indefinite treatment would increase the risk of autoimmune toxicity (16). It may be sufficient to provide pulsed immunotherapy on a periodic basis to extinguish accumulating neoplasms before they become clinically detectable.

It is likely that any utility of immune checkpoint blockade for cancer prevention would be most obvious in patients at high risk because of inherited DNA repair deficits known to lead to increased mutational burden in each cell at risk for transformation. However, because some cancers have high-mutational burden in the absence of inherited deficits in DNA repair, and furthermore, because increased tumor mutational burden is not always required for advanced cancers to respond to checkpoint inhibition, we cannot rule out the possibility that checkpoint inhibition could reduce cancer risk in other populations. Although we recognize the inherent limitations of an “n = 1” case report, this patient's history suggests that “immuno-interception” as a strategy to reduce cancer risk deserves further study.

No potential conflicts of interest were disclosed.

One of the Editors-in-Chief of Cancer Prevention Research is an author on this article. In keeping with AACR editorial policy, a senior member of the Cancer Prevention Research editorial team managed the consideration process for this submission and independently rendered the final decision concerning acceptability.

Conception and design: M.N. Pollak, J.G. Mancuso

Development of methodology: M.N. Pollak, J.G. Mancuso

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): W.D. Foulkes, J.G. Mancuso

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.N. Pollak, W.D. Foulkes, J.G. Mancuso

Writing, review, and/or revision of the manuscript: M.N. Pollak, W.D. Foulkes, J.G. Mancuso

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): J.G. Mancuso

Study supervision: M.N. Pollak

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