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Immune checkpoint suppression in special populations in cancer treatment
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Immune checkpoint suppression in special populations in cancer treatment.
Immunotherapy is revolutionizing the treatment of cancer.
It improves the overall survival ( OS ) and progression-free survival ( PFS ) of a variety of cancers , such as melanoma, non-small cell lung cancer ( NSCLC ), renal cell carcinoma, and Hodgkin Lymphoma.
Immune checkpoint inhibitors ( ICIs ) activate T cells to exert anti-tumor effects in the body by blocking inhibitory receptors and ligands including PD-1, PD-L1 and CTLA-4.
But they can also cause immune-related adverse events ( IRAE ) by changing the immune environment in the body , such as checkpoint inhibitor pneumonia, immune-related thyroiditis, hepatitis, myocarditis, enteritis, etc.
Among patients treated with anti-PD-1/PD-L1 inhibitors, the incidence of IRAE was 26.82%.
Due to concerns about potential side effects and curative effects, patients with organ transplantation, tuberculosis, HIV, and previous autoimmune diseases and mental illnesses were excluded from prospective randomized trials.
In addition, pediatrics and obstetrics also need more attention.
Faced with patients who are not eligible for clinical trials, many oncologists cannot provide precise treatment plans.
Fortunately, some studies have evaluated the safety and effectiveness of immunotherapy in special populations receiving immunotherapy, including organ transplant patients, pregnant women, pediatric patients, tuberculosis ( PTB ) patients, HIV patients, and autoimmune diseases and Patients with mental illness.
Although the pathogenesis of these diseases is related to the immune system, there are big differences in clinical practice, such as treatment, IRAE risk, and clinical outcome.
Understanding the role of immunotherapy in these special populations can help oncologists to carry out their clinical work.
Solid organ transplantation ( SOT ) or hematopoietic stem cell transplantation is not uncommon among cancer patients.
Cancer is the second leading cause of death for all SOT recipients, indicating that there is a large cancer burden in this population.
Clinical studies have shown that PD-1 or PD-L1 expression is related to allograft tolerance.
Therefore, whether ICI will destroy immune tolerance and cause serious post-transplant complications remains a question.
Existing studies have found that patients treated with ICIs show different clinical responses.
According to Abdel Wahab et al., Received solid organ transplant cancer in 39 patients, 16 patients ( 41% ) after the treatment ICI now allograft rejection, a total of 8 patients (21%) IRAE occurred, and these adverse reactions occurred in patients who did not have allograft rejection.
The median OS of patients without rejection was 12 months, and the median OS of patients with rejection was 5 months (P=0.03).
De Bruyn et al. also reported similar conclusions. They found that among the 48 patients with advanced cancer who had undergone organ transplantation treated with ICI, those who received liver transplantation (37%) and kidney transplantation (45%) had rejection.
These results indicate that patients have a higher risk of allogeneic rejection after transplantation.
Some people can tolerate ICI treatment, while others experience severe post-transplant complications. The PD-1/PD-L1 axis may play a key role in allograft rejection.
Has been demonstrated, the donor tissue PD-L1 may be allogeneic to the receptor expressed on T cells of PD-1 receptor interaction thereof, so that the receptor downregulation alloreactive T cell responses and limit rejection .
PD-1/PD-L1 inhibitors can disrupt the balance of the immune microenvironment, leading to allograft rejection in SOT patients treated with ICIs.
Patients during pregnancy
The incidence of cancer during pregnancy is approximately 24.5 per 100,000. If cancer occurs during pregnancy, both the mother and the fetus have a greater risk of death.
It is important to weigh the advantages of the mother and the fetus in order to prolong survival and reduce teratogenicity.
Recent studies report that most pregnant women are already in their late stages when they are diagnosed.
For patients with positive driver genes, targeted therapy may be a good choice, while immunotherapy is a possible treatment option for pregnant women with negative driver genes.
Maternal and infant immune tolerance involving complex mechanisms may have the same approach as cancer immune checkpoint blockade.
It has been proven that blocking PD-L1 can reduce the survival rate of allogeneic fetuses. Therefore, some people worry about whether immunotherapy will disrupt the mother’s tolerance to the fetus by blocking immune checkpoints.
Currently, there are 2 cases showing the possibility of applying immunotherapy in pregnant women. The first case was a case of metastatic melanoma at 7 weeks of pregnancy.
She received nivolumab plus ipilimumab and successfully delivered a healthy baby. Menzer et al. also reported similar cases of metastatic melanoma occurring at 18 weeks of pregnancy.
The patient was treated with nivolumab plus ipilimumab, but the patient’s condition slowly deteriorated and he died of underlying disease the day before delivery.
Fortunately, premature girls were born without deformities or intrauterine growth delays.
These reports indicate that certain patients can benefit from the use of ICIs. Due to ethical challenges, different cultures and laws, clinical trials are difficult to conduct.
It is very important for doctors to balance benefits and risks and make decisions in a multidisciplinary environment.
In developing countries, cancer is one of the main diseases leading to death of children and adolescents. Pediatric cancer treatment is significantly different from adult cancer treatment.
The most common types of cancer in children include acute lymphoblastic leukemia ( ALL ) ( 26% ), brain and central nervous system ( CNS ) tumors ( 21% ), neuroblastoma ( 7%) ) And non-Hodgkin’s lymphoma ( NHL ) ( 6% ), while the most common cancers in adolescence are Hodgkin’s lymphoma ( HL ) ( 15% ), thyroid cancer ( 11% ), brain and central nervous system tumors ( 10% ) and testicular germ cell tumors (8 % ).
Traditional treatments for childhood cancer include surgery, chemotherapy, and radiotherapy. Compared with adult cancer, immunotherapy has no obvious effect in the first-line treatment of childhood cancer.
However, for many patients with refractory and recurrent tumors, immunotherapy has become a viable treatment option.
Immune checkpoint inhibitors, such as anti-PD-1 or anti-CTLA-4 antibodies, are similar in safety to adults, but the drug’s response rate to solid cancer in children is much lower than that of adults.
It has been reported that among 155 children with PD-L1-positive solid tumors or lymphomas ( including PD-L1-negative advanced melanoma ), all children were treated with pembrolizumab.
At the end of treatment, 9 out of 15 HL patients achieved objective curative effect ( 60.0% ), and 8 out of 136 other lymphoma or solid tumor patients achieved objective curative effect ( 5.9% ).
The adverse reaction was proved to be acceptable. Tolerable.
The results of a phase I study ( NCT01445379 ) of pediatric patients with melanoma and other solid tumors who received CTLA-4 blockade therapy showed that they were well tolerated with anti-CTLA-4 treatment, but there was no objective response.
However, 2 cases showed that the treatment of recurrent and refractory tumors in children showed obvious efficacy and safety.
It has been confirmed that the levels of PD-1, PD-L1 and PD-L2 in solid tumors in children are low.
The adverse reactions of childhood cancer patients to PD-1/PD-L1 inhibitors may be related to the low expression of PD-1/PD-L1.
Compared with chemotherapy and radiotherapy that may cause neurological dysfunction, bone deformities and short stature, immunotherapy has less long-term toxicity and is more conducive to the healthy growth of children.
Immunotherapy for childhood cancer is still in the exploratory stage.
By determining the best targets and accurate biomarkers, it is believed that immunotherapy will completely change the treatment of childhood cancer and improve the survival rate and quality of life of childhood cancer patients.
According to WHO statistics, more than 10 million people worldwide suffered from tuberculosis ( TB ) in 2018 .
In the past 20 years, the incidence of active tuberculosis among lung cancer patients was 1.9%.
Compared with other cancers, patients with esophageal cancer, multiple myeloma, lung cancer, pancreatic cancer, leukemia, head and neck cancer, and lymphoma are more likely to develop tuberculosis.
In the past few years, some cases have reported acute tuberculosis in cancer patients treated with nivolumab or other PD-1/PD-L1 inhibitors.
At the same time, a patient with advanced lung adenocarcinoma developed tuberculous pericarditis after nivolumab treatment.
Currently, there are no large clinical trials that can provide accurate data on the incidence of tuberculosis reactivation after immunotherapy.
Two hypotheses are proposed regarding the activation mechanism of TB.
First, blocking the PD-1/PD-L1 pathway may lead to the proliferation of T cells, which in turn produces anti-Mycobacterium tuberculosis ( Mtb ) IFN-γ, thereby restoring the anti-tuberculosis specific immune response.
Second, the activation of tuberculosis leads to diffuse lymphocyte infiltration.
These assumptions are still to be determined. In short, it is very important to pay attention to potential Mycobacterium tuberculosis infection in patients and clinically screen for latent tuberculosis.
Patients with autoimmune diseases
About 11.3% of patients with advanced cancer have a history of autoimmune diseases.
Existing studies have shown that PD-1/PD-L1 and CTLA-4 are related to the occurrence of autoimmune diseases.
Therefore, the use of ICIs in cancer patients with autoimmune diseases ( PAD ) raises concerns, because further immune stimulation may lead to new autoimmune manifestations or underlying symptoms in PAD patients.
A study in 30 PAD cancer patients treated with ICIs showed that 33% ( 10/30 ) of the patients experienced grade 3-5 IRAE, and 10% ( 3/30 ) of the pictures also experienced autoimmunity Disease onset and IRAE.
Among the 30 patients, there were 1 complete response ( CR ) and 5 partial response ( PR ). The median PFS was 3 months, and the median OS was 12.5 months.
Another item of 52 PAD cancer patients treated with ICIs , 38% ( 20/52 ) of patients had autoimmune episodes ( 2 patients stopped treatment ), and 29% ( 15/52 ) of patients had conventional IRAEs ( 10% is level 3 ).
Response was observed in 33% ( 17/52 ) of patients, with a median PFS of 6.2 months.
These studies show that cancer patients with PAD can tolerate ICIs.
For cancer patients with stable PADs, reducing immunosuppressive therapy during the initiation of ICIs will not reduce the efficacy of cancer treatment.
The safety of using ICIs in patients with severe autoimmune diseases is still unclear. High-dose steroids may reduce the efficacy of ICIs.
Therefore, when facing these patients, cooperation between PAD experts and oncologists is very important.
Compared with healthy people, people infected with HIV have a 69% higher risk of cancer. However, cancer patients infected with HIV are always excluded from clinical trials.
In the past few years, there have been some clinical trials evaluating the safety and effectiveness of immunotherapy in cancer patients infected with HIV.
In a study of 30 HIV patients with Kaposi’s sarcoma ( KS ), NHL and other types of tumors ( NCT02595866 ), all patients were treated with pembrolizumab.
The main purpose is to evaluate the safety of pembrolizumab in cancer patients receiving antiretroviral therapy (ART). The results showed that 22 patients ( 73% ) had grade 1-2 IRAE, and 6 patients ( 20% ) had grade 3 IRAE.
The HIV of all participants was controlled. Regarding the patient’s tumor response, there were 1 case of CR, 2 cases of PR, 17 cases of SD, 8 patients developed progressive disease ( PD ), and 2 patients could not be assessed.
In another study of 7 lung cancer patients infected with HIV, nivolumab ( n=2 ) and pembrolizumab ( n=5 ) were treated.
All patients received antiretroviral therapy during immunotherapy. The patient’s tumor response included PR ( n=3 ), SD ( n=2 ) and PD ( n=2 ), and only 4 patients had grade 1-2 IRAE.
These results indicate that the immunotherapy of HIV-infected patients is as effective as the general population and has good safety, similar to that of general cancer patients.
In short, unless there are special circumstances, HIV-infected cancer patients receiving antiretroviral therapy can be treated similarly to ordinary cancer patients using immunotherapy.
Patients with mental illness
According to the “Manual of Diagnosis and Statistics of Mental Disorders”, Alzheimer’s disease ( AD ), depression, bipolar disorder and anxiety are all mental illnesses.
Several recent studies have proven the link between the immune system and mental illness. CNS-specific T cells can promote hippocampal neurogenesis, spatial learning and memory abilities through microglia activation.
Animal studies have shown that by blocking the PD1/PD-L1 axis, the cognitive deficits of the 5XFAD AD mouse model are successfully alleviated and the pathological changes in the brain are reduced.
This result indicates that ICIs may have good clinical applications in AD patients.
When facing health threats, cancer patients are prone to emotional distress such as depression and anxiety.
According to reports, the incidence of depression in cancer patients varies from 1% to 50%, depending on the cancer type, stage, treatment, and different depression grading scales.
Both depression and anxiety are immune-mediated inflammatory diseases, which have been extensively studied from the perspective of chemokines, cytokines, and the number of immune cells.
In addition, the relationship between mental illness and the immune system is still unclear.
There are currently no clinical trials or cases evaluating the efficacy and safety of immunotherapy for patients with mental illness.
This requires further research in the future.
With the rapid expansion of ICI therapy in special populations, it is very important to clearly understand the safety and effectiveness of ICI therapy in these populations.
Because people like clinical trials are often isolated from screening conditions, we have limited data.
In these limited reports, SOT patients receiving immunotherapy are at risk of allograft rejection.
There is no evidence that immunotherapy is associated with the risk of fetal malformations.
Therefore, it is recommended to use CTLA-4 and/or PD-1 inhibitors in cancer patients during pregnancy, provided that the benefits to the mother are very large and exceed the substantive theory for the fetus risk.
When treated with ICIs, patients with Mtb show a potential risk of developing acute PTB. Tuberculosis screening is important before immunotherapy.
Existing autoimmune diseases are not an absolute contraindication to ICI treatment, but patients with life-threatening autoimmune diseases or patients with myasthenia gravis may not be a good choice for ICI treatment.
For HIV-infected cancer patients receiving ART treatment, the efficacy and safety of immunotherapy are similar to those of general cancer patients.
Therefore, it can be considered that HIV is not a contraindication to ICI treatment. Cancer patients with mental illnesses such as AD may be potential beneficiaries of immunotherapy.
Finally, clinicians can refer to these results and provide patients with appropriate solutions by balancing potential benefits and toxicity risks. At the same time, multidisciplinary consultations are needed to make treatment decisions.
1.Immune Checkpoint Inhibitors in SpecialPopulations. Technol Cancer Res Treat. 2021; 20: 15330338211036526.
Immune checkpoint suppression in special populations in cancer treatment
(source:internet, reference only)