Unlocking the Potential of Immune Checkpoint Inhibitors: A Pioneering Case Series on the Role of Immunotherapy in Microsatellite-Instability-High Colorectal Cancer

Abstract

Immune checkpoint inhibitors have demonstrated unprecedented activity in a small percentage of patients with colorectal carcinoma, which is attributed to microsatellite instability-high (MSI-H) status characteristic of a deficient DNA mismatch repair (dMMR) system. The case series illustrates the use of ICIs with neoadjuvant treatment of locally advanced CRC as well as with conversion treatment of oligometastatic disease in the setting of a tertiary care center. This included three patients with MSI-H/dMMR CRC treated with pembrolizumab or a combination of ICIs, where there was remarkable regression of the tumor masses with the making of tumors amenable to surgical intervention, which heretofore had been considered unresectable. These three examples underscore how treatment with ICIs may revolutionize the landscape of therapy for the management of patients with MSI-H/dMMR CRC, especially in neoadjuvant and conversion therapeutic approaches. Despite these encouraging results, challenges remain in optimizing both timing and patient selection to address these issues and make ICIs a standard-of-care treatment for MSI-H/dMMR CRC.

Introduction

Colorectal cancer is one of the most common cancers in the globe whereby despite advances in treatment, the mortality from the malignancy remains high. However, over the last decade, immunotherapy has revolutionized the landscape of cancer medicine, especially for a particular group of CRC patients diagnosed as having MSI-H. These patients present with a dMMR system, which leads to the phenomenon of a hypermutated tumor phenotype and higher presentation of neoantigens; therefore, they make the best candidates for immune checkpoint inhibitors.

The success of ICIs, especially pembrolizumab and nivolumab, in the treatment of advanced or metastatic CRC with MSI-H/dMMR, opens the horizon for their use in earlier stages of the disease. Clinical studies like NICHE2 and NICHE3 have shown great responses to ICIs in the neoadjuvant setting for localized CRC that allows the possibility of establishing ICIs as a standard pre-surgery treatment. In addition, these encouraging outcomes appear to offer the use of conversion therapy in locoregionally advanced CRC and oligometastatic disease where surgery alone would most probably not be curative.

The present report aims to share a series of cases regarding the experience of patients with MSI-H/dMMR CRC treated with ICIs in a tertiary care center, and elucidate the outcomes, challenges, and unanswered questions that arise when contemplating ICIs as an adjunct treatment strategy. Additionally, this will outline their position about achieving resectability for locally advanced or oligometastatic diseases.

Case Series Overview

Patient Selection and Diagnostic Criteria

The current case series consists of three patients diagnosed with CRC at our tertiary center. All the patients underwent molecular testing and proved to have an MSI-H/dMMR status. Baseline staging is composed of imaging studies, tumor marker assessment, and histopathological confirmation of the diagnosis of CRC. Confirmation of the inclusion of MSI-H/dMMR status was done by immunohistochemistry for mismatch repair proteins and by PCR for microsatellite instability.

These are a mix of clinical scenarios, ranging from locally advanced CRC in the neoadjuvant setting to oligometastatic disease. Therefore, the treatment history and response to ICIs are of great importance from the perspective of real-world application to this distinct subset of patients with CRC.

Case 1: Neoadjuvant Immunotherapy in Locally Advanced CRC

This 62-year-old man was diagnosed as having locally advanced rectal carcinoma, classified under T3N2M0. The man came in with the complaint of passing tarry stools and altered bowel habits. On the initial colonoscopy, there was a large mass protruding into the lumen of the rectum, and biopsy results confirmed adenocarcinoma. Given the MSI-H/dMMR status, he was an excellent candidate for neoadjuvant immunotherapy. Since the ICIs appear to be effective in clinical trials such as NICHE2, the patient underwent pembrolizumab monotherapy with 200 mg every three weeks before the definitive surgical intervention.

She was brought in six cycles of pembrolizumab and demonstrated a dramatic shrinkage of her tumor with a near-complete radiologic response. The subsequent surgical resection had only residual microscopic disease as an impressive pathological response. She recovered well post-operatively, remained disease-free at 18 months of follow-up, and did not require adjuvant chemotherapy.

It is still not clear whether such deep tumor regression by ICIs translates into the reduction of the need for more aggressive therapies such as chemoradiation in MSI-H/dMMR CRC.

Case 2: Conversion Therapy in Locally Advanced CRC with Lymph Node Involvement

A 55-year-old woman was admitted with locally advanced CRC, wherein the tumor had substantially involved the lymph nodes (T3N2M0). She underwent treatment in the form of chemotherapy with CAPOX, comprised of capecitabine and oxaliplatin, for three cycles; nonetheless, the progression of the disease was noted. Based on subsequent molecular testing, it was found that she was MSI-H/dMMR, and thus therapy was switched to pembrolizumab alone.

At the sixth cycle of immunotherapy, imaging studies showed a remarkable reduction of the primary tumor and lymphadenopathy. Surgical resection became feasible, which had been excluded at the outset because of extensive lymphadenopathy. The pathological evaluation after surgery indicated a partial response with viable tumor cells still present but in fewer numbers.

In that sense, the case of a patient clarifies the idea of ICIs as conversion therapy in which previously unresectable tumors can be made operable. Patients who may have arrived at the point of "untreatable" according to traditional chemotherapy routes may confront new approaches opened by these potentials.

Case 3: Oligometastatic Disease and Immunotherapy

A 60-year-old male with CRC and oligometastatic liver disease is the third patient. Initial staging showed a T3N1M1 lesion with limited liver metastases. Upon failure of first-line FOLFIRI chemotherapy, the patient was subjected to MSI-H/dMMR testing, which was positive, and he was therefore treated with pembrolizumab and nivolumab in combination because of the significant burden of the disease.

Imaging four months into treatment showed marked regression of both the primary tumor and the liver metastases to offer possible curative surgery. She underwent resection of both the primary and metastatic sites, and she achieved a complete pathological response to the liver metastases while maintaining minimal residual disease at the primary site.

The case will demonstrate how, in the context of conversion therapy not only in locally advanced CRC but even in oligometastatic settings, transformation with ICIs may pave the way toward long-term survival and even a cure for some of the patients.

Discussion

The cases presented in this series underscore the profound impact of ICIs in treating MSI-H/dMMR CRC, particularly in the neoadjuvant setting and as conversion therapy for advanced disease. Key considerations that arise from these cases include:

Timing of Immunotherapy: In all three cases, immunotherapy was initiated at different stages of disease management—neoadjuvant, conversion, and in the metastatic setting. These diverse scenarios raise the question of optimal timing for ICI initiation. Should immunotherapy be started earlier in the treatment algorithm for MSI-H/dMMR CRC, or reserved for refractory cases? The findings from NICHE2 suggest that early initiation, even in localized disease, may confer significant benefits in terms of tumor downstaging and surgical outcomes.

Pathological Responses: The impressive pathological responses observed in these cases, including near-complete responses and significant tumor regression, reflect the potential for ICIs to revolutionize treatment for MSI-H/dMMR CRC. These responses parallel the results seen in the NICHE trials, where major pathological responses were achieved in a high percentage of patients. This raises important considerations regarding the necessity of adjuvant therapy in patients who achieve such responses.

Immunotherapy as Conversion Therapy: The success of ICIs in converting unresectable tumors to operable ones, as demonstrated in Cases 2 and 3, suggests a role for immunotherapy beyond metastatic disease. This opens the door to potentially curative surgeries in patients who might otherwise face limited treatment options. Further studies are needed to validate these findings and to determine the long-term outcomes of patients who undergo surgery after ICI treatment.

Challenges and Future Directions: Despite the promising results of immunotherapy in MSI-H/dMMR CRC, several challenges remain. These include determining which patients will benefit most from ICIs, understanding mechanisms of resistance, and addressing the need for biomarkers to predict response. The role of ICIs in non-MSI-H/dMMR CRC also remains unclear, with ongoing trials exploring combination strategies to expand the efficacy of immunotherapy to a broader CRC population.

Conclusion

It shows the promise of immune checkpoint inhibitors in changing the fate of treatment approaches in MSI-H/dMMR colorectal cancer. Whether it be neoadjuvant or conversion therapy, a glimmer of hope exists for patients with advanced or locally aggressive disease. More studies are thus for these cases to establish immunotherapy as the new standard of care and further resolve the many questions generated by optimal treatment strategies.

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