Immune Checkpoint Inhibitors, and in combination with JAK inhibitors: The modelling for the future

D. Suryaprabha*

Chief Clinical Pharmacist & Assistant Manager – Clinical Research, Kauvery Hospitals, India

 

*Correspondence: M: +91 98414 86267;
email: [email protected]

Abstract

Background:. Checkpoint Immunotherapy has revolutionized cancer treatment in the past decade for many cancer patients. This review explains how the immune checkpoint inhibitors (ICIs), when combined with JAK Inhibitors, give a good outcome.

Methods: The recent studies related to the combination therapy were reviewed.

Conclusion: The paper explains resistance to the ICIs, the current trends in this combination therapy and  some newer approaches.

Keywords: Janus Kinase (JAK), Immune checkpoint inhibitors (ICIs), Signal, Immune checkpoint therapy (ICT)

Background

Checkpoint immunotherapy has revolutionized cancer treatment in the past decade for many cancer patients[1]. But not all cancer patients respond to immune checkpoint inhibitors. So, scientists explored whether adding Janus Kinase Inhibitors (JAKi would improve efficacy..In two separate clinical studies, researchers found that adding JAK inhibitors to ICI did improve patients’ responses to the cancer [2]

What is Immunotherapy?

A kind of therapy that uses substances to stimulate or suppress the immune system to help the body fight cancer, infection, and other diseases.

What is an immune check point?

Immune checkpoint is a kind of signal for regulating the antigen recognition of T cell receptor (TCR) in the process of immune response. Immune checkpoint contains two kinds of signals:

(1) Co-stimulatory immune checkpoint: stimulating immune progress, such as CD28, ICOS, and CD137;

(2) Co-inhibitory immune checkpoint: inhibiting immune progress, such as PD1, CTLA-4, and VISTA.

When immune system is attacking pathogens, these immune checkpoint molecules can protect the normal tissues from damage. The cancer cells cleverly escape from immune attack by dysregulating immune checkpoint related proteins. Immune checkpoint therapy relys on functioning immune system with agonists of co-stimulatory signals or antagonists of inhibitory signals.

What are Immune Check Point Inhibitors?

Immunotherapy drugs called immune checkpoint inhibitors work by blocking checkpoint proteins from binding with their partner proteins. This prevents the “off” signal from being sent, allowing the T cells to kill cancer cells.[3]

How do they work in Cancer?

One of the most substantial advances in cancer therapy, in the last decades, was the discovery of a new layer to the approach to immunotherapy. This heralded the arrival of immune checkpoint inhibitors (ICIs), which can specifically activate immune cells by targeting immune checkpoints. Immune checkpoints are a type of immunosuppressive molecules expressed on immune cells, which can regulate the degree of immune activation and avoid autoimmune responses. ICIs, such as anti-PD-1/PD-L1 drugs, have shown inspiring efficacy and broad applicability across various cancers. [4] One such drug acts against a checkpoint protein called CTLA-4. Other immune checkpoint inhibitors act against a checkpoint protein called PD-1 or its partner protein PD-L1. Some tumours turn down the T cell response by producing lots of PD-L1.

What are the common ICIs in use, and against what cancers, when and how?

Examples of Immune Checkpoint Inhibitors include pembrolizumab, ipilimumab, nivolumab and atezolizumab.

Immune checkpoint inhibitors were approved to treat some people with a variety of cancer types, including:

Breast cancerLung cancer
Bladder cancerRenal cell cancer
Cervical cancerSkin cancer, Including Melanoma
Colon cancer
Head and neck cancerStomach cancer
Hodgkin lymphomaRectal cancer
Liver cancerAny solid tumour

How are the clinical outcomes so far? 

Immunotherapy has become the central pillar of cancer therapy. Immune checkpoint inhibitors (ICIs), a major category of tumour immunotherapy, reactivate preexisting anticancer immunity. Initially, ICIs were approved only for advanced and metastatic cancers in the salvage setting after or concurrent with chemotherapy at a response rate of around 20–30% with a few exceptions. With significant progress over the decade, advances in immunotherapy have led to numerous clinical trials investigating ICIs as neoadjuvant and/or adjuvant therapies for resectable solid tumours. The promising results of these trials have led to the United States Food and Drug Administration (FDA) approvals of ICIs as neoadjuvant or adjuvant therapies for non-small cell lung cancer, melanoma, triple-negative breast cancer, and bladder cancer, and the list continues to grow. [7]

What is ICI resistance?

The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high proportion of patients who do not benefit from ICI therapy due to a lack of response when first treated (primary resistance) or detection of disease progression months after objective response is observed (acquired resistance).

Immune Checkpoint Therapy: The Clinical Success Story

Immune checkpoint therapy (ICT) has dramatically altered clinical outcomes for cancer patients and conferred durable clinical benefits, including cure in a subset of patients.

Development of the fundamental understanding of mechanisms of T cell function opened the field of ICT that has provided durable clinical benefits to many patients across different tumour types. To achieve the goal where ICT can render cure to a maximum number of patients with cancer, we will need to integrate clinical research with discovery science, adopting reverse translation strategies.

In addition to improving our understanding of T cell-mediated anti-tumour functions, we will need to delve into the intricacies of other immune and non-immune pathways that cumulatively impact the anti-tumour immunity.

Currently, most of the approvals of ICT are in the metastatic setting with few as adjuvant therapy. Exploring the utility of ICT in earlier disease settings could potentially help with surgical downstaging and even organ preservation. Overall, clinical success of ICT underlines the importance of developing biologically informed therapeutic strategies to improve clinical outcomes for patients.[5]

Why were JAKi combined with ICI?

Aside from the exciting findings of the early phase trials reported by [both groups], they provide a great deal of data with complex analyses of immune responses. Because not all cancer patients respond to a leading type of cancer immunotherapy drug, known as an immune checkpoint inhibitor, scientists explored whether adding janus kinase (JAK) inhibitors – drugs that treat chronic inflammation – could help. In two separate clinical studies, researchers found that adding JAK inhibitors did improve patients’ responses to cancer checkpoint inhibitor immunotherapies. [2]

What are JAKi?

JAK inhibitors belong to a family of medicine called DMARDs (disease-modifying antirheumatic drugs). The FDA to treat rheumatoid arthritis approves three JAK inhibitors, baricitinib (Olumiant), tofacitinib (Xeljanz), and upadacitinib (Rinvoq).

Examples of JAK inhibitors are baricitinib, tofacitinib, fedratinib, abrocitinib, ruxolitinib, ritlecitinib, Upadacitinib, Peflicitinib, filgotinib, Pacritinib, Decernotinib, Daricitinib ect.

Fig (1): Classification of JAK Inhibitors

How do they work in cancer?

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is implicated in the development and progression of many cancers [1,2]. Hyperactivation of STAT transcription factors, has been reported in both hematologic malignancies and solid tumors, including cancers of the breast, lung, liver, head and neck, and stomach, among others [3-8]. For many of these cancers, increased activation of the JAK/STAT signaling pathway is associated with a worse prognosis, including increased recurrence and reduced overall survival[1,9,10]. Given the strong association between JAK/STAT hyperactivity and the development and prognosis of multiple cancers, STATs and their upstream activators, JAKs, are being extensively explored as targets for cancer therapy[8].

Has the combination worked?

Research has described the different mechanisms that can provide benefits when we consider combination regimens. One mechanism, synergy, is when the combined effects of more than one treatment are greater than the sum of the individual effects of each treatment.

The other mechanism, called additivity, occurs when the combined effects are roughly equal to the sum of the individual effects. The Cancer Discovery Research concluded that for several recent combination therapy approvals, including ICI combinations, additivity was responsible for the incremental benefit of the combination therapy. [6]

Treating Cancer types, including breast cancer, bladder cancer, cervical cancer, colon cancer, head and neck cancer, Hodgkin lymphoma, liver cancer, lung cancer, renal cell cancer, skin cancer, including melanoma, stomach cancer, rectal cancer.

Fig (2): PD-1/PD-L1 pathway contributes to tumour immune escape, enabling tumours resistant to immune response.

Where is the evidence?

In two separate clinical studies, researchers found that adding JAK inhibitors did improve patients’ responses to cancer checkpoint inhibitor immunotherapies. “Aside from the exciting findings of the early phase trials reported by [both groups], they provide a great deal of data with complex analyses of immune responses,” write Massimo Gadina and John O’Shea in a related Perspective. “It will be exciting to see how such sophisticated data might be used in the clinic and to inform research.” Immune checkpoint inhibitors (ICIs) work by blocking checkpoint proteins on T cells that otherwise prevent the immune system from targeting and killing cancer cells. ICIs have substantially improved the treatment of some types of cancers. However, not all patients respond to these immunotherapies. Cancer patients often have chronic inflammation and immunosuppression, which can limit ICI treatment response.

In two independent clinical studies, researchers investigated whether using JAK inhibitors or jakinibs, which prevent inflammation from inside cells, could improve antitumor responses of anti-PD-1 ICI immunotherapy in cancer patients. Divij Mathew and colleagues conducted a phase II clinical trial to investigate the use of the JAK1 inhibitor itacitinib in combination with the anti-PD-1 ICI pembrolizumab as a first-line treatment for metastatic non-small cell lung cancer (NSCLC).

Mathew et al. found that delayed administration of itacitinib following treatment of pembrolizumab improved the response of immunotherapy. According to the findings of the trial, which included 21 patients with treatment-naïve NSCLC, median progression-free survival was nearly 2 years, compared to the 6.5 to 10.3 months reported in other trials with only ICI. In a separate study, Jaroslav Zak and colleagues report results from a phase I/II clinical trial in patients with relapsing-refractory Hodgkin lymphoma who had previously received ICI and were unresponsive or showed mixed response. Zak et al. focused on the use of a combination of ruxolitinib, a JAK1 and JAK2 inhibitor, and the anti-PD-1 drug nivolumab. According to the findings, administration of ruxolitinib 8 days before the start of nivolumab therapy resulted in improved clinical efficacy in patients that had previously failed ICI immunotherapy. Among the 19 patients who participated, overall survival was 87% at 2 years compared to previous reports of 23.8% with ICI alone. [2, 9, 10, 11]

What other advances in this direction are expected in the future?

The combinational strategies are distinct for different tumors, so initiating combinational treatment of ICIs and targeted drugs should be carefully carried out. Looking forward to the future, ICIs combined with ADCs may be an innovative strategy for cancer treatment based on the results of the KATE2 study [76]. A continuous phase III trial, KATE3, investigating the efficacy of atezolizumab plus T-DM1 in PD-L1-positive, HER2-positive advanced breast cancer, is ongoing. Another phase II trial (NCT04468061) is recruiting TNBC patients for treatment by combining pembrolizumab and sacituzumab govitecan (a Trop2-ADC). ADCs will exert more important roles in cancer immunotherapy, which has the advantages of both antibodies and cytotoxic drugs. In addition, other immunotherapies may play an important role in the future, including CAR-T immunotherapy, NK cell, and Treg therapy. Despite limited successes to date with ICI monotherapy, immunotherapy still holds promise for the treatment of GBM. Individualized combination therapies may ultimately transform GBM care and improve patient outcomes. ICIs possess the potential to serve as the critical elements of these combinations.

Conclusion

The above discussion explains the important and current trends ICIs resistance, of combination therapy and newer approaches. In an attempt to overcome resistance to immune checkpoint inhibitors (ICI), an ever-increasing number of trials are exploring combination treatment approaches. Combination treatment with other ICIs, TKIs/anti-VEGFs, chemotherapy, locoregional therapies, and RT are promising approaches to enhance anti-tumour efficacy.

References

  • Jaroslav Zak et al., JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.Science 384,eade8520(2024). DOI: 10.1126/ science.ade8520
  • Mathew, D., et al. (2024) Combined JAK inhibition and PD-1 immunotherapy for non–small cell lung cancer patients. Science. doi.org/10.1126/science.adf1329.
  • https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors
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D. Suryaprabha
Chief Clinical Pharmacist & Assistant Manager – Clinical Research

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