# Challenges in the Evolving Role of Calreticulin as a Promising Target for Precision Medicine in Myeloproliferative Neoplasms

## TL;DR

This paper reviews progress in targeting calreticulin mutations in blood cancers and highlights challenges in developing effective therapies.

## Contribution

The paper outlines recent advances in immunotherapy targeting CALR mutations in MPNs and identifies key challenges for clinical translation.

## Key findings

- Monoclonal antibodies against CALR show promising clinical responses with manageable toxicity.
- Bispecific antibodies and CAR T-cell therapies offer preclinical potential against CALR-mutant cells.
- Vaccination approaches have shown limited clinical benefit and remain uncertain.

## Abstract

Calreticulin (CALR) mutations in myeloproliferative neoplasms (MPNs) create unique opportunities for targeted therapy. The most advanced approach involves monoclonal antibodies specifically designed to recognize the CALR neoepitope, with early clinical trials showing encouraging results. Additional preclinical data derives from bispecific antibodies that redirect T cells against CALR-mutant cells, precision antibody–drug conjugates delivering cytotoxic payloads, and CAR T-cell therapies. Vaccination against CALR-derived peptides has shown immune activity but limited benefit, and its role remains uncertain. This review discusses these advances and outlines the challenges that must be overcome to translate them into routine clinical practice.

More than a decade after its discovery, advances have been made in understanding the oncogenic role of mutant CALR in BCR::ABL1-negative myeloproliferative neoplasms (MPNs). Disease biology has proven to be distinct from other MPN subtypes, with meaningful differences that have created opportunities for therapeutic targeting of CALR-mutant clones. Among the approaches under investigation, immunotherapy has advanced furthest into clinical development and holds promise. Several strategies are now being explored, including monoclonal antibodies directed against the CALR neoepitope, T-cell–redirecting bispecific antibodies, precision antibody–drug conjugates, vaccination approaches, and CAR T-cell therapies. Early-phase clinical trials with fully human anti-CALR monoclonal antibodies (e.g., INCA033989) have shown very promising hematologic and molecular responses with manageable toxicity. In preclinical models, bispecific antibodies and CAR T-cell therapy offer additional avenues to exploit the selective cell-surface localization of mutant CALR. By contrast, vaccination strategies have so far demonstrated limited clinical efficacy, and their potential in clinical practice remains challenging. At the same time, the complexity of CALR-driven disease raises key questions, including whether anti-CALR therapies can shift treatment goals beyond thrombotic risk reduction, how best to monitor clonal burden, and how to address immune escape. In this review, we highlight the latest therapeutic advances in CALR-mutated MPNs while outlining the critical unmet needs that will shape the future of care for these patients.