In the past decade or so, the field of tumor immunology and immunotherapy has undergone a renaissance, and after countless successful and frustrated attempts, it has been found that immunotherapy does have an incomparable advantage over traditional anti-tumor therapies, which can prolong progression-free survival (PFS) and overall survival (OS).
After continuous efforts, immunotherapy is now at the forefront of cancer research and is recognized as an important tool in anti-tumor armaments. However, "immunotherapy has obvious complexities and uncertainties."
There is growing evidence that 4% to 29% of all cancer patients with various histology may experience tumor outbreaks after undergoing immunotherapy. This new tumor response model, known as hyper-progression, is a potentially harmful side effect of immunotherapy, accelerating disease progression in some patients.
So what is hyper-progression, and is it true that hyper-progress caused by immunotherapy is true? Or is it fictional? Or is it another fact? How to deal with the super progress?
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How does immunotherapy fight tumors?
Under normal circumstances, the immune system can recognize and clear tumor cells in the tumor microenvironment, but in order to survive and grow, tumor cells will adopt different strategies to suppress the body's immune system and cannot kill tumor cells normally, thus surviving the various stages of the anti-tumor immune response.
While we tend to think of immunotherapy as the latest medical achievement, it originated decades ago. But in fact, the origin of immunotherapy can be traced back to the Qin Dynasty in China around the third century BC. Although difficult to prove, there is still some scarce written reference to purposeful vaccination with smallpox virus to prevent smallpox disease.
Today, immunotherapy has metamorphosed from one complex experimental protocol after another to many previously untreatable, malignant, and "off-the-shelf" first-line treatment options.
Unlike traditional chemotherapy, which targets the biological processes of cancer cells, immunotherapy seeks to enhance the body's natural immune defenses against cancer. This is achieved by training innate immune cells to recognize and eliminate cells with tumor-specific antigens, providing external stimuli to enhance immune-mediated tumor cell lysis or eliminating signals indicated by tumor cells to suppress the immune response.
At present, tumor immunotherapy includes monoclonal antibody immune checkpoint inhibitors, therapeutic antibodies, cancer vaccines, cell therapy and small molecule inhibitors.
Immunotherapy leads to hyper-progression of the disease
SCI published a case in which a 65-year-old male lung cancer patient was EGFR/ALK negative and had high PD-L1 expression (98%). It is reasonable to say that patients with K drugs (pembrolizumab, Keytruda) are very likely to benefit, but strangely, after 21 days of medication, the patient's primary lesion increased from 40mm to 80mm, not only did not have the effect, but also underwent rapid progression, and on the 37th day, unfortunately died.
People can't help but sigh that the distance between "magic medicine" and "poison" is between the first line.
We all know that the immune checkpoint inhibitors (ICI) represented by PD-1/PD-L1 monoclonal antibodies such as K drugs have made remarkable achievements in inhibiting tumor growth and prolonging the survival time of patients, and immunotherapy has become the brightest "star" in the field of anti-cancer, but in fact, there is a problem we have to face under its glamorous appearance, that is, "hyper-progress".
Definition of hyper-progress:
At the 2016 Annual Meeting of the European Society of Oncology (ESMO), research on over-advances in immunotherapy was first reported. The concept of hyper-progress (HPD) was then explicitly proposed by the Champiat team at the Gustav Rusi Institute, and since then, many scholars have reported on the phenomenon of hyper-progression and supplemented and refined its definition.
At present, there is no clear definition of hypermaturity, and it is more recognized that Kato et al. proposed the following definition in the CCR, and tumor progression after immunotherapy meets the following three conditions:
- In immunotherapy, the tumor progresses for less than two months;
- Tumor burden increased by more than 50% compared to baseline;
- Tumors grow more than 2 times faster after immunotherapy than before.
(Picture shows the potential outcome of immunotherapy.) (A) Shades of gray indicate that the disease is stable and that changes in the tumor are minimal or absent; shades of green indicate a persistent response, with the tumor continuing to contract over time; and shades of blue indicate false progression, with the initial enlargement of the tumor seen in imaging and shrinkage in subsequent scans. (B) The orange shade indicates a non-lasting response, and the initial contraction of the tumor is considered a response; however, over time, the tumor begins to progress; the yellow shadow indicates tumor progression, and the tumor enlarges in subsequent scans; and the red shadow indicates a hyper-progressive disease, where the tumor growth becomes expanded on imaging. ）
Mechanism of hyper-progression:
In the immunotherapy and Hyperprogression: Unwanted Outcomes, Unclear Mechanism. paper published by David A. Knorr and Jeffrey V. Ravetch, two separate immunodeficiency models of mouse T cells were used and demonstrated that mice carrying H460 non-small cell lung cancer tumors were treated with rat IgG2a anti-pd-. 1 After antibody treatment, tumors grow faster and are associated with an increase in tumor invasive CD45 cells. This suggests that myeloid cells expressing pd-1 in TME may be involved in this process.
The authors concluded that hyper-progression is sustained by bone marrow cells within tumor-associated macrophages (HMEs) and points to a potential FcR-dependent mechanism.
But mice are not humans, and testing various ICI in immunodeficient mice remains a serious limitation of these preclinical models. Most of the existing studies reporting HPD are single-arm, without control, and there are no valid data to demonstrate the mechanism of tumor hyperpromension caused by immunotherapy.
Until now, the reasons why immune drugs cause tumor hyper-progression have been explored. However, there are several speculative explanations:
- PD-1/PD-L1 is likely to be only one of the main molecular mechanisms in tumor immunity, but mutations or polymorphisms in genes encoding immune modifiers may create complex and diverse immune pathways in the body, contributing to the occurrence of hyperprovor progression;
- PD-1/PD-L1 inhibitors may promote tumor proliferation in some cases. In fact, the immune system plays a dual role in the body, which may lead to the development of cancer by inducing DNA damage, the production of free radicals, etc.
(Picture shows case studies of over-progressive patient scans.) A case study of a woman in her 60s with kidney cell carcinoma. Nilumab shows significant tumor progression. (A) Baseline scan prior to nirolizumab therapy shows invasive retroperitoneal mass involving right renal blood vessels. (B) Restaging scans performed 6 weeks after nivolumab therapy showed an increase in retroperitoneal mass and new liver metastases. (C) Follow-up scans conducted 10 weeks after the start of nirolumab showed a widespread increase in the size of the retroperitoneal mass and a significant increase in the size and number of new liver metastases, confirming disease progression. Abbreviation: PD-1, programmed cell death 1. ）
Another fact that immunotherapy leads to hyper-progression of the disease
- False progress
False progression (PP): refers to the initial increase in the size of the tumor or the appearance of new lesions after starting immunotherapy for a period of time, but this is not due to the tumor continuing to proliferate, but due to more immune cells infiltrating into the interstitium around the tumor cells, causing the tumor to appear larger, and after a period of immunotherapy, the "tumor" gradually shrinks.
This particular pattern of response was first described in melanoma patients treated with ipilimumab, and then in many other malignancies over the past few years, including a small percentage of patients with advanced non-small cell lung cancer (NSCLC).
Many cases of pseudo-progressive non-small cell lung cancer have been reported in the literature, particularly during treatment with ipilimumab, whether primary or secondary, or metastatic central nervous system.
A false progression rate of 4.6 percent was reported in patients treated with NSCLC by ipilimumab, and Nishino reported a lower PP rate (0.6 percent) when evaluating responses in patients with nivolumab and pembrolizumab. Consistent with this evidence, Ferrara and colleagues reported a 4.7 percent rate in 2018, suggesting that the actual incidence of false progression in this setting has not been established, but it appears to be a rare phenomenon where PP may be associated with favorable long-term outcomes after immunotherapy, but further evaluation is needed.
(Schematic diagram illustrates pseudo-aggression and excessive progression under immune checkpoint blockade therapy, as well as pathophysiological hypotheses of hyper-progression))
The physiological pathology of this phenomenon can be explained by the penetration of transient immune cells in tumor tissues that grow until there is a sufficient immune response, or that is associated with edema and necrosis. Similarly, the development of new lesions may be evaluated at baseline with T cell penetration into lesions where radioactivity is undetectable or unmeasurable.
There are concerns that evaluating the best imaging techniques for PP may be more helpful than classical imaging in terms of the difference between PP and real progression. For commonly used techniques, suspicious PP requires sufficient vigilance: on the one hand, continuing immunotherapy may lead to a late response, on the other hand, overtreatment can be harmful and may lead to missed potentially useful treatments.
Discernment can also be obtained by histological evaluation, as lesions that expand due to PP may lead to intensive immune cell penetration, but there is no determination of the right time to perform a biopsy, nor is it feasible or indivisible, and considering these aspects, only very critical cases should be considered.
In addition to imaging and pathology, to discern PP from true progression, other features, such as the patient's presenting condition, should also be considered: PP should not be accompanied by clinical exacerbations, as this may reflect a true hyperpathy.
Principles of response to immunotherapy over-progression
(1) First and foremost, inform the patient. Patients receiving immunotherapy have the right to know that hyperprovity may be one of the "adverse reactions" of immunotherapy and that it may lead to adverse effects;
(2) Before clinical immunotherapy, genetic testing is required to assess the risk of hyper-progression, in the process of immunotherapy, especially in the first 6-8 weeks before the start of immunotherapy, it is necessary to pay close attention to the patient's situation (> 65-year-old people need special attention), actively supplemented by dynamic monitoring and efficacy evaluation, clinically should be combined with the patient's body sensation, whether the symptoms are aggravated, or puncture when necessary, to find out whether the tumor tissue is infiltrated with immune cells or true progression, so as to judge the next step of medication.
(3) Once hyper-progression is confirmed, immunotherapy must first be stopped, actively treated with glucocorticoids, and other symptomatic adjuvant therapy is given at the same time to maintain the patient's basic vital signs, and immunosuppressants can be used in severe cases. When the condition is stable, other antineoplastic regimens may be considered.
Hyper-progression is not a unique phenomenon in immunotherapy, and the occurrence of hyper-progression has been reported in articles in chemotherapy, radiotherapy and even targeted therapy.
However, the specific mechanism of hyper-progression in immunotherapy is still unknown, and there are still many controversies about hyper-progression, but overall, the phenomenon of hyper-progression in immunotherapy seems to be limited to about 10% of patients.
The proposal of ultra-advanced immunotherapy may not be a bad thing, but may be a good news for tumor patients.
We believe that the hyper-progression of anti-PD-1/PD-L1 therapy tells us an important point in tumor biology: "Understanding this phenomenon can not only be used to identify patients who should not be treated with anti-PD-1/PD-L1, but most importantly, it may be used to develop new treatments."
By studying and ultimately understanding the mechanisms that lead to hyper-progression, we researchers believe that in the near future, we researchers should be able to identify pathways that can be targeted at turning hyper-progressive patients into responders.