Cancer Immune Therapy for Philadelphia Chromosome-Negative Chronic Myeloproliferative Neoplasms

Abstract

<jats:p>Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) are neoplastic diseases of the hematopoietic stem cells in the bone marrow. MPN are characterized by chronic inflammation and immune dysregulation. Of interest, the potent immunostimulatory cytokine interferon-α has been used to treat MPN for decades. A deeper understanding of the anti-cancer immune response and of the different immune regulatory mechanisms in patients with MPN has paved the way for an increased perception of the potential of cancer immunotherapy in MPN. Therapeutic vaccination targeting the driver mutations in MPN is one recently described potential new treatment modality. Furthermore, T cells can directly react against regulatory immune cells because they recognize proteins like arginase and programmed death ligand 1 (PD-L1). Therapeutic vaccination with arginase or PD-L1 therefore offers a novel way to directly affect immune inhibitory pathways, potentially altering tolerance to tumor antigens like mutant CALR and mutant JAK2. Other therapeutic options that could be used in concert with therapeutic cancer vaccines are immune checkpoint–blocking antibodies and interferon-α. For more advanced MPN, adoptive cellular therapy is a potential option that needs more preclinical investigation. In this review, we summarize current knowledge about the immune system in MPN and discuss the many opportunities for anti-cancer immunotherapy in patients with MPN.</jats:p>

The immune landscape in BCR‐ABL negative myeloproliferative neoplasms: inflammation, infections and opportunities for immunotherapy

“…There are many new therapies in clinical development for MPNs, including novel JAK inhibitors that are more selective for JAK2, ‘add‐on’ drugs that improve efficacy of ruxolitinib both in ruxolitinib‐naïve patients and in those who have a suboptimal response, and new targets (Table I and reviewed in Venugopal and Mascarenhas) 67 . Many of these have anti‐inflammatory activity, such as the bromodomain and extra‐terminal motif (BET)‐inhibitor CPI‐0610· 68 In the next section, we outline some emerging targeted immunotherapy strategies that aim to ameliorate the deficiencies in anti‐tumoral immunity described above (Fig 2; also reviewed in Holmstrom et al 69 …”

Myeloid-Derived Suppressor Cells and Mesenchymal Stem/Stromal Cells in Myeloid Malignancies

“…Furthermore, the immune checkpoint PD-1 is induced in activated T-cells, and the binding with PD-L1-expressing cells provokes T-cell anergy [239]. The use of anti-PD-1 and anti-PD-L1 blocking antibodies has shown extraordinary results in solid tumors and hematological disorders [240,241]. PD-1-blocking antibodies have been tested in MDS and AML, especially in combination with the hypomethylating agents, such as 5-aza-2 deoxycitidine, which have shown promising results in relapsed/refractory AML [242].…”

“…Importantly, IL1RAP-CART cells exhibit cytotoxicity against leukemic stem cells without an apparent effect on CD34 + stem cells [253]. Nevertheless, the treatment of myeloid malignancies with CART is challenging because it requires surface antigens that are genuinely expressed by the neoplastic cells [240].…”

A case of JAK2V617F-positive essential thrombocythemia where allele burden was reduced by a PD-1 inhibitor

“…Furthermore, the cytotoxic T-lymphocyte-associated protein 4 inhibitor, ipilimumab, which is another checkpoint inhibitor, increased CD8-positive cells, reduced regulatory T cells, and exerted an antitumor effect on hematological tumors, even in one patient with MPN that recurred after allo-SCT [23]. The immune system of a patient with MPN and the mechanism by which antitumor immunity is disrupted are gradually becoming clear [24]. Therefore, immune checkpoint inhibitors may become an important therapeutic strategy for MPN in the future.…”