Hyperprogressive disease (HPD) in immune checkpoint inhibitor therapy

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Hyperprogressive disease (HPD) in immune checkpoint inhibitor therapy

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Hyperprogressive disease (HPD) in immune checkpoint inhibitor therapy.  In recent years, immune checkpoint inhibitors (ICIs) have proven to be one of the most promising and effective immunotherapies.

They target specific molecules, such as programmed cell death protein 1 (PD-1) or its ligands. (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), etc., to rebuild the anti-tumor response and prevent tumor cells from evading immune surveillance.

Antibody drugs including nivolumab, pembrolizumab, durvalumab and atezolizumab have been approved for the treatment of various types of cancers such as non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma.

However, more and more retrospective studies have found that some patients treated with ICIs will have abnormal reactions, including accelerated proliferation of tumor cells and rapid disease progression, with poor prognosis.

This unexpected adverse event is called hyperprogressive disease (HPD), and its occurrence indicates that ICIs are not good for some cancer patients. HPD is very common, with an incidence of between 4% and 29% in several types of cancer.

However, the pathogenesis of HPD is still poorly understood, and clinical predictors of HPD have not yet been determined. The emergence of HPD poses new challenges to the current methods used to assess the efficacy of ICIs.

Evidence and controversy of HPD

In 2016, the incidence of HPD was reported for the first time in a phase I trial of anti-PD-1/PD-L1 inhibitors at 9% (12/131). In this study, HPD has nothing to do with tumor burden or tumor type at baseline, and it occurs more frequently in patients over 65 years of age. In another retrospective analysis report of 34 HNSCC patients, the highest incidence of HPD reached 29%. In addition, in the clinical trials CheckMate 057, CheckMate 227 and CheckMate 141 comparing ICIs and standard chemotherapy, evidence of HPD was found. Although the clinical diagnostic criteria of HPD are different in different studies, they all compare the tumor growth before and after immunotherapy in a short period of time.

Since HPD clinical studies are mostly retrospective, it is still controversial whether HPD is an independent mode of response after ICIs treatment. The main controversy is whether HPD is a natural process of tumors or an accelerated growth process that occurs after ICI treatment. In most trials, there is no reference data on tumor growth rate (TGR) before the start of ICIs, and the intersection of the two survival curves is thought to be because chemotherapy is more effective than ICIs, not because of HPD itself.

In addition, a study reported a similar proportion of HPD in a cohort of 850 NSCLC patients treated with docetaxel or atezolizumab, suggesting that HPD may be caused by a poor prognosis rather than immunotherapy. At present, although data on HPD has been accumulated, there is no universal standard for its definition. Future studies should evaluate the best HPD criteria to identify patients who cannot benefit from ICI treatment and those who are most likely to benefit from it. It is important to collect imaging therapy and tumor growth kinetics data before ICI treatment, and to distinguish HPD from inherently aggressive disease or false progression.

Definition and diagnosis of HPD

It is crucial to detect and distinguish progression, false progression, and HPD at an early stage. At present, the evaluation and diagnosis of HPD are mainly based on the parameters related to pretreatment tumor kinetics and early changes after the start of immunotherapy, including TGR, tumor growth kinetics (TGK) and treatment failure time (TTF).

The first appearance of HPD was based on RECIST1.1, which was defined as an increase of TGR by ≥2 times after immunotherapy, while Ferrara et al. established different standards to increase TGR by 50%. TGR is the ratio of tumor size changes in a given time interval and is a predictor of overall survival in clinical practice. The evaluation of TGR is based on RECIST. However, there is no correlation between RECIST and TGR changes before and after treatment. Therefore, RECIST 1.1 is not the most accurate method for evaluating the effect of immunotherapy.

The evaluation of TGK is similar to that of TGR, and it also measures the change in the total maximum diameter of the target lesion. However, this HPD evaluation method is limited to the target area of ​​the tumor, and does not consider the appearance and changes of lesions in the non-target area. In actual clinical practice, TGR data before immunotherapy cannot be obtained, and the ratio cannot be distinguished by basic imaging analysis of tumor size changes. Therefore, methods based on TGR and TGK cannot be used to evaluate new lesions in tumor growth. . Importantly, these methods only use radiological standards, which may miss other response modes. Therefore, some studies have combined clinical and radiological criteria, and TTF less than 2 months can also be used as a surrogate indicator for the assessment of HPD.

Other studies have quantified the number of senescent CD4+ T cells (Tsens) in the circulation before and after ICI treatment. An increase in the number of Tsens before immunotherapy indicates a response, while a decrease in the number of Tsens after the first treatment cycle indicates a good response. On the contrary, the proliferation of Tsens indicates progress. In general, a combination of multiple methods may provide the most valuable assessment. Although the current HPD diagnosis is relatively inaccurate, it still provides usable information for further research.

False progress

The concept of tumor pseudo-progression was first observed in patients treated with the non-immunotherapy drug temozolomide. However, this phenomenon did not accompany real tumor progression. False progression is not true tumor progression, but growth defined by radiographic imaging. The pathological features are immune cell infiltration, edema, and necrosis around the tumor. Given that at the beginning of clinical trials, beneficial treatments are often interrupted due to false progress, it is necessary to distinguish between false progress and HPD.

In addition to the inflammation caused by the invasion of tumor immune cells, the delayed immune response may also lead to false progress, especially in patients whose tumors have resolved after false progress. Regarding the incidence of false progress in the treatment of solid tumors with ICIs, there have been several studies. Among melanomas, 3.7–15.8% of patients treated with ICIs have abnormal immune responses or false progress. In addition, it is reported that the incidence of false progression in patients with NSCLC, urothelial carcinoma, HNSCC, and mesothelioma is 0.6-5.8%, 1.5-7.1%, 1.8%, and 6.9%, respectively. Although false progress mainly occurred in patients who received single checkpoint inhibitors, false progress was also observed in patients who received dual immunotherapy.

The analysis of circulating tumor DNA (ctDNA) levels can be used as an effective tool to distinguish disease progression, HPD and false progression. Unlike HPD, false progress is manifested as a decrease in ctDNA genome instability. In a study of 125 melanoma patients treated with ICI, the ctDNA profile distinguished false progression from HPD with a high degree of sensitivity (90%) and specificity (100%).

In general, false progress has a good prognosis and should be determined as soon as possible to avoid delay in disease due to early interruption of treatment. At the same time, it is also important to understand the likelihood of real tumor progression.

Biological and clinicopathological factors of super-progress

It is important to identify potential predictors of HPD. This can avoid adverse reactions caused by ICIs, and has important clinical significance for prolonging the survival and quality of life of patients.

The study found no correlation between HPD and baseline tumor burden, previous treatment, tumor histology, type of immunotherapy, or number of metastatic sites. So far, five clinical variables (age, female, higher serum lactate dehydrogenase (LDH) concentration, metastatic load, and local cell recurrence in the radiotherapy area) have been identified as possibly related to HPD, in addition to specific genomes Mutations, such as MDM2/MDM4 amplification and EGFR mutations.

Age seems to be related to the occurrence of HPD. Patients with HPD are significantly older than those without HPD. 19% of patients over 65 have HPD, while only 5% of patients under 64 have HPD. These results indicate that elderly patients benefit less from ICIs than young people. The number, diversity, phenotype and function of T cells change, and T cell immunity declines with age. At present, the specific relationship between HPD and aging is not fully understood.

In addition, studies have found that HPD is related to radiotherapy. In the existing anti-PD-1/PD-L1 studies, 50% of patients with local recurrence developed HPD, while only 6.25% of patients without local recurrence developed HPD. Almost all HPD cases occur in patients who relapse in the irradiated area, but the underlying mechanism of this phenomenon is unclear.

Genome mutations may be potential genomic markers related to immunotherapy and HPD. Some mutations (such as TERT, PTEN, NF1, and NOTCH1) have good clinical results (TTF ≥ 2 months); on the contrary, mutations of EGFR, MDM2/4, and DNMT3A are associated with worse results (TTF <2 months).

Some researchers pay attention to CD8+ T cells in peripheral blood to find potential predictors. The study found that the number of effector CD8+ T cells decreased in HPD patients, while the number of depleted tumor-reactive CD8+ T cells (TIGIT+PD-1+) increased. The results show that CD8+ T cell depletion is one of the potential mechanisms of ICIs therapy to accelerate tumor growth, and the severity of T cell depletion can predict HPD. In addition, the number of CD28 in HPD patients is also significantly up-regulated, which indicates that CD4+ T cell immunity may be a powerful predictor of HPD.

The underlying mechanism of HPD

At present, the molecular mechanism of HPD is unclear. Some studies have explored various hypotheses or mechanisms of HPD from different perspectives. These mechanisms can work independently or complement each other. It is of great significance to clarify the molecular mechanism of HPD. HPD can be caused by many factors, including the characteristics of tumor cells, the status of the patient’s immune system, and the patient’s current or past treatment history.

Up-regulation of PD-1+Tregs

In the case of infection or cancer, anti-inhibition or immune compensation is a self-stabilizing mechanism. Immunosuppressive factors, such as Tregs, can maintain anti-infection or anti-tumor immunity and reduce the adverse effects of ICIs. A study analyzed gastric cancer tumor tissues before and after ICI treatment and found that the number of Tregs in the tissues of HPD patients increased, indicating that ICI treatment may activate these Tregs. In an in vitro gastric cancer study, it was observed that when PD-1 on Tregs is knocked out or blocked, Tregs can proliferate and promote immune suppression against tumor immune cells. The above studies indicate that PD-1 may mediate the occurrence of HPD, thereby inhibiting anti-tumor immunity.

T cell exhaustion

T cell exhaustion is defined as T cell dysfunction, weakened ability to recognize and eliminate antigens, and upregulation of inhibitory receptors including PD-1, TIM3, TIGIT and LAG3. The overexpression of these inhibitory receptors may be the key mechanism of PD-1 treatment resistance. With the overexpression of these inhibitory receptors, CD8+ T cells show severe dysfunction in the production, proliferation and migration of cytokines.

Tsens increase

In a study of anti-PD-1/PD-L1 drug therapy for NSCLC patients, the number of senescent T cells at baseline was detected, and patients with relatively high Tsens developed HPD. In contrast, the tumor regressed significantly in patients with lower Tsens. The results show that the number of Tsens in patients before immunotherapy can predict the risk of HPD. The baseline number of Tsens may represent the overall situation of a pre-existing effector T cell with potential anti-tumor ability.

MDM2/4 amplification and EGFR mutation

Studies involving multiple tumor types have shown that the activation of oncogenes, such as MDM2/4 amplification, is related to the occurrence of HPD. MDM2/4 promotes the proteasome ubiquitin-dependent degradation of p53, and the loss of p53 activity is an important driving factor for tumorigenesis. ICIs can increase the production of IFN-γ in tumor sites, and IFN-γ can increase the expression of MDM2/4, which suggests that the MDM2/4-IFN-γ/p53 axis may mediate the occurrence of HPD.

The activation of EGFR is usually accompanied by the up-regulation of PD-1/PD-L1 or CTLA-4 to promote tumor immune escape. The objective response rate of EGFR mutation patients to anti-PD-1 therapy is relatively low, about 3.6%. This may be related to the activation of EGFR, which can promote the stability of PD-L1 and prevent its degradation. However, the link mechanism between EGFR mutations and HPD is still unclear.

The role of Fc receptors

The immune microenvironment is closely related to HPD. Severe combined immunodeficiency (SCID) animal model studies have found that compared with Nivolumab Fab fragments, Nivolumab promotes tumor growth, while no substantial tumor growth or HPD is observed in Nivolumab Fab fragments. Further research found that M2 macrophage aggregation only occurred in the lesions after nivolumab treatment, not the Fab fragment of nivolumab.

In another study of malignant melanoma, knocking out Fcγ receptors (FcγR) in mice can enhance the anti-tumor effect of anti-PD-1 antibodies, directly showing the correlation between FcγR and ICIs. It has been suggested that FcγR IIb has an adverse effect on human anti-PD-1 immunotherapy and can lead to HPD. Studies have found that FcγRI induces immune tolerance by regulating inflammatory cytokines and plays a role in the production of M2 macrophages to promote tumor growth.

Imbalance of immunosuppressive cytokines

Tumor-derived extracellular bodies have been shown to induce PD1+ macrophages to produce IL-10 and inhibit the function of CD8+ T cells. Analysis of the tumor tissues of 104 NSCLC patients with HPD revealed that a large number of M2 type PD-L1+ macrophages secreted IL-10, which mediates the occurrence of HPD by depleting PD-1 antibodies.

IFN-γ can enhance the immune resistance of tumors by increasing the expression of PD-L1 in cancer cells. The release of IFN-γ from T cells can increase the selective pressure of cancer cells, leading to acquired defects in the IFN-γ pathway, and gain resistance to ICIs by losing sensitivity to IFN-γ. In addition, the loss of IFN-γ signal in CD8+ T cells also observed resistance to immunotherapy. These results prove the potential role of IFN-γ in HPD.

Type 3 intrinsic lymphocytosis

ILC3 is specifically increased in HPD tumors. ILC3s can respond to cytokine stimulation without the need for specific antigens. According to reports, ILC3 can produce IL-17 and IL-22, thereby promoting cancer progression. Studies have shown that the presence of ILC3 in the tumor microenvironment is associated with a high risk of breast cancer lymph node metastasis. This abnormal inflammatory environment may be related to the poor efficacy of ICIs, but its relationship with HPD is unclear.

The role of neoantigens

Neoantigens lead to higher cell heterogeneity, which helps immune cells target and eliminate tumor cells. Acquired resistance to ICIs and HPD can also be predicted by neoantigens. The dysfunction of neoantigens may promote tumor metastasis and recurrence. Screening these neoantigens may predict treatment resistance and HPD.

Other mechanisms

Other factors such as LDH may be related to HPD. High LDH levels represent tumor hypoxia and acidification of the extracellular environment. High LDH levels and acidic environments may affect the function of antibodies and the conformation of antigens, thereby affecting the specificity and affinity of ICIs. Some studies have found that the gut microbiota affects the role of ICIs in melanoma patients. As we all know, the microbiome is a key regulator of inflammation and immune response, and may play an important role in cancer treatment.

Possible strategies to avoid HPD

Due to the poor prognosis of HPD patients, there is an urgent need to develop strategies to reduce or eliminate its harm to patients. In clinical practice, it is necessary to pay more attention to changes in patients’ conditions and to evaluate the efficacy of ICIs treatment. First of all, patients who need to be treated with ICIs need to fully understand the risks of HPD, because the incidence of HPD is high, and some patients may refuse treatment due to adverse consequences. In addition, current tumor assessment methods for immunotherapy do not include TGK, which is the key to early recognition of HPD. It can enable a considerable part of patients who meet the definition of HPD to continue to receive treatment.

The existing cancer disease monitoring and evaluation system urgently needs to be changed. In treatment, early detection of HPD and timely replacement of ICIs may be the only remedy to avoid patient risks. However, false progress can also affect the recognition of HPD. Therefore, the obvious tumor progression at the first imaging after the start of immunotherapy does not necessarily mean that treatment must be terminated, because patients with false progress may benefit from this treatment. The evaluation of MDM2/4 amplification, EGFR mutation and CNI score before treatment helps to select patients who may develop HPD. However, the predictive value of these biomarkers has not yet been verified.

NK cell therapy will attenuate PD-L1 positive tumor cells in vivo, and the combined use of NK cells and ICIs may be another option for HPD patients. In addition, in the Checkmate227 trial, patients who used nivolumab combined with chemotherapy had a lower risk of progression than those who used nivolumab combined with ipilimumab. Chemotherapy may help prevent patients from developing ICI resistance and HPD, and this possibility deserves further study.

Summary

There are still many controversies about HPD, but it is known to occur in many tumor types and almost all malignant tumors, and is related to poor prognosis. More and more retrospective studies have shown that HPD is caused by ICIs, and HPD is a serious adverse reaction in ICI treatment, which limits the clinical application of ICI. HPD induced by ICI is complex, therefore, it is necessary to explore the etiology and pathogenesis of HPD, and to develop prediction and detection methods to prevent the suspension of immunotherapy.

In short, HPD is a new phenomenon, and its underlying mechanism remains to be elucidated. In addition, the clinical relevance and predictive factors of HPD need to be further studied. HPD provides challenges and opportunities for the development of new tumor biotherapies, and will also promote research to improve the effectiveness and safety of ICIs. In-depth study of this issue is important to protect cancer patients from the potentially harmful side effects of ICI therapy.

(source:internet, reference only)

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