PD-1, as an immunotherapy, mobilizes a person's own immune system to fight against cancer cells, which generally takes 2 months to take effect (with a small probability of 1.3-1.5 months). It is important to stay on it for 2 months! Don't joke with your life! Don't wait for chemo to get to the point where you are very sick before choosing PD1 . The side effects of PD-1 inhibitors are much less severe than those of conventional radiotherapy, with the incidence of grade 3-4 serious adverse effects halved or more. The most common side effects are "flu" like symptoms: fever, malaise, dizziness, generalized muscle pain, drowsiness, etc. These symptoms occur in about 1/3 of the patients, and can be gradually relieved after symptomatic treatment.
Patients with EGFR mutations: EGFR inhibitors combined with PD-1 are not recommended, and interstitial pneumonia/immune pneumonitis is 5-fold higher . The rate of fulminant progression is very low and most patients presenting with fulminant progression have MDM2 gene amplification.
There is no evidence that short courses of hormones at low doses decrease PD-1 efficacy, and it is now generally accepted that glucocorticoids decrease the effectiveness of PD-1/PD-L1 antibodies, that glucocorticoids should not be used during PD-1/PD-L1 antibody therapy to prevent irAEs, and that glucocorticoids should be discontinued at least 2 weeks prior to the initiation of antibody therapy.
Instead, several large foreign studies have shown that it is the antibiotics that really affect efficacy.The use of broad-spectrum antibiotics during PD-L1/PD-1 therapy may lead to a substantial reduction in efficacy! It may be that antibiotics, including amides, quinolones, and macrolides, affect the patient's gut flora! But, then again, can't an oncology patient who develops an infection while on PD-1 antibodies be on antibiotics? It should still be used properly and regulated according to the doctor's instructions. In a clinical trial of the PD-1 antibody Opdivo against non-small lung cancer[1], researchers found that lung cancer patients who smoked cigarettes, were EGFR-na?ve, and had KRAS mutations were more likely to benefit.
It is not recommended to spend a lot of money on full genetic testing for PD-1; it is better to blindly test for PD1, which is less expensive. There are a number of indicators that can predict the efficacy of PD-1 inhibitors, and the following three are relatively reliable:
(1) PD-L1 expression level. Using pathological sections, do immunohistochemistry to see the expression rate of PD-L1 in pathological tissues. Note that it is not a genetic assay, but immunohistochemistry; it is not measuring PD-1, but PD-L1. the higher the PD-L1 expression rate, the higher the effective rate. In addition, the expression of the PD-L1 molecule is very dynamic and unevenly distributed in tumor tissue, which can easily lead to false-negative results.The PD-L1 assay itself does have some problems: biological aspects such as inter- and intratumoral heterogeneity, and interventional therapies affecting expression. More evidence now suggests that it is not as effective and that the use of PD1 can be tried blindly.
(2) MSI/dMMR: take the pathology slice, use genetic testing method to measure MSI; or use immunohistochemistry method to measure dMMR. gastrointestinal patients, it is recommended to measure this index. MSI/dMMR positive gastrointestinal patients, suitable for PD-1 inhibitor treatment.
(3) mutation load TMB: take the pathology section (really can't, can also take peripheral blood instead), do mutation gene detection, the more mutations contained in the unit length of DNA, the higher the efficiency. The more mutations per unit length of DNA, the higher the efficiency.
The higher the TMB, the more neoantigen production that ends up being recognized by T cells. However, TMB is actually a quantitative indicator of the likelihood that tumor cells will produce abnormal proteins, or "neoantigens," through the accumulation of mutations, and a mutation that produces neoantigens is an immunogenic mutation, not an absolute. For example, even if the TMB is low, a patient with a KRAS mutation has won the "lottery", and the KRAS G12D mutation is able to produce a neoantigen that binds with high affinity to HLA-C*08:02 and is recognized by T-cells, rather than simply having a high TMB. Therefore, the KRASG12D mutation is more likely to benefit from PD-1 therapy.
PD-1/PD-L1 antibodies kill tumors while damaging their own tissues, causing a series of toxic side effects called immune-related adverse events (irAEs). irAEs are characterized by a broad spectrum of clinical manifestations and lagging effects. Broad-spectrum refers to the fact that irAEs can occur in any tissues and organs of the body, and common manifestations include chills, fever, fatigue, itchy skin, rash, leukodystrophy, oral ulcer, diarrhea, hearing loss, numbness of the limbs, blurred vision, coughing, respiratory distress, elevated aminotransferases, and disorders of thyroid and adrenal glands.
Lagging refers to the fact that irAEs appear weeks to months after starting antibody therapy, when patients are recuperating at home and the side effects of PD-1/PD-L1 antibodies are easily overlooked and missed, leading to serious consequences. Although there is a pattern to the timing of irAEs, it is important to note that irAEs can occur at any point during treatment and during a period of discontinuation, and should not be taken lightly.
Systematic monitoring Early detection of irAEs depends on regular monitoring and follow-up. The detection of irAEs is based on regular monitoring and follow-up. routine blood, urine, stool, biochemistry, thyroid function, pituitary function, adrenal cortex function, electrocardiogram and chest radiographs should be performed prior to the start of antibody treatment, and the above items should be reviewed regularly after the start of antibody treatment. diarrhea, abdominal pain, headache, and changes in visual acuity should be examined by colonoscopy, cranial brain, and pituitary MRI, as appropriate. Although the incidence of immune-related toxicity is high, the vast majority of side effects are mild and can be recovered with symptomatic treatment. With regular monitoring, timely detection, and aggressive management, PD-1/PD-L1 antibody therapy is safe and feasible. Some studies have found that the greater the side effects, the higher the probability of achieving long-term remission.
Specific adverse effects of immunotherapy should be noted, primarily PD-1/PD-L1 antibody-associated pneumonitis - i.e., "immune pneumonitis", "interstitial pneumonitis". ". Patients with non-small cell lung cancer are advised to wear a mask when going out to prevent infection. After starting the medication, for early detection, perform chest imaging and serum markers and oxygen saturation, please pay attention to the clinical manifestations and the manifestation of self-conscious symptoms. If clinical symptoms such as shortness of breath, dyspnea, cough, fatigue, fever, and abnormal lung sounds are confirmed, perform a chest X-ray, monitor oxygen saturation, etc., and observe the patient thoroughly. If abnormalities are recognized, please perform a chest X-ray, chest CT, tests such as serum markers, and consult with a respiratory specialist if necessary.
All of the Class I patients and 8 Class II patients were relatively mild and required only outpatient care, while the remaining 18 patients required hospitalization. For the class I patients, 15 went into remission by stopping the medication, and the remaining 2 and most of the patients in class II and above were able to control their disease with glucocorticoids either orally or by intravenous infusion in combination with anti-TGF-β, anti-IL-6, and other treatments if necessary. However, five patients with grade III and above could not be controlled with glucocorticoids alone and required the addition of more potent immunosuppressive drugs (infliximab or infliximab combined with cyclophosphamide).
Twelve patients with mild adverse effects (grades I and II) were re-treated with PD-1/PD-L1 monotherapy after treatment (9 patients discontinued the drug and 3 had glucocorticoids) and complete remission of the pneumonia, 9 of whom did not have a recurrence of the pneumonia, whereas the other 3 had a recurrence of the drug-associated pneumonia, but were cured again both by discontinuation of the drug and by administration of glucocorticoids. Drug-associated pneumonia.
For these unfortunate patients, the conventional treatment is high-dose hormones in combination with a variety of common immunosuppressants (e.g., mycophenolate mofetil, infliximab, etc.) and the strongest supportive therapy available. But despite this, extreme cases of death due to the violent immune inflammation caused by PD-1 antibodies have occurred from time to time.
In 2016, the top medical journal NEJM reported that the incidence of immune cardiac inflammation due to PD-1 antibodies alone is about six in 10,000; this rises to about three in 1,000 with the combination of PD-1 antibodies and CTLA-4 antibodies. Once severe cardiac inflammation occurs, death is almost certain, with rare reports of successful resuscitation at home and abroad. Professor Andrew Haydon of the University of Melbourne, Australia, at the end of the mountain and at the end of his rope, took the risk of giving the patient " horse anti-thymocyte globulin ", together with conventional hormones, immunosuppressant drugs, and the strongest supportive therapy, successfully resuscitated a case of malignant, refractory, and ferocious immune cardiac inflammation.
Penicillamine and hormone and hormone alone in the treatment of interstitial lung fibrosis, the efficacy of the comparison is not significantly different, but the side effects of penicillamine + hormone group is significantly less than that of the hormone group alone, but the penicillamine should be done before the application of penicillamine skin test, pay attention to the side effects, the main side effects are gastrointestinal reactions and allergic reactions.
TIM3 positive expression also showed a significant time-dependence with the duration of anti-PD-1 treatment, with low TIM3 positive expression before treatment and during the treatment-sensitive period, and a significant increase in TIM3 positive expression after the development of drug resistance. In drug-resistant tumors, TIM3 expression was also significantly correlated with the degree of PD-1 antibody binding in T cells, and the higher the degree of PD-1 antibody binding in T cells, the stronger the TIM3 expression.
There is a strong positive correlation between the size of the tumor burden and the number of Ki-67-positive killer T cells in the patient's blood - the larger the tumor, the more Ki-67-positive killer T cells in the blood.
After in-depth analysis of the mechanism of PD-1 antibody anti-cancer, the key to the efficacy of PD-1 antibody neoadjuvant therapy is the massive expansion and migration of pre-existing tumor-specific lymphocytes in peripheral blood and tumor tissues to the tumor foci, which exerts an anti-cancer effect. This inference can be graphically and objectively reflected by the expression of molecular markers such as PD-1, CTLA-4 and TIM-3 on lymphocytes, the elevation of Ki-67 index, a representative marker of proliferative capacity, and the increase of lymphocytes, or TILs, in tumor tissues. By detecting changes in the proportion of Ki67-positive cells among CD8-positive T cells in the peripheral blood before and 1-3 weeks after PD-1 treatment, it is possible to predict whether the PD-1 antibody is effective or not . The proportion of Ki67-positive CD8 T-cells increased significantly in patients who responded to treatment, whereas in those who did not respond, there was little change in this cell subset . IL-8 is an important cytokine released from tumor tissues, and its concentration correlates with both tumor load and the intensity of the immune response.After PD-1 antibody administration, if it is effective and the tumor is killed, the released IL-8 decreases dramatically. Therefore, using the change in IL-8 concentration in peripheral blood, it is possible to predict earlier whether the PD-1 antibody has taken effect. After receiving PD-1 antibody treatment, if the drug works, the tumor load will decrease, and then the concentration of oncogenic mutations in the blood will also decrease. Conversely, if the drug does not work, ctDNA concentrations in the blood will not decrease significantly or will even increase.
For patients with lung cancer, the survival rate of patients with stage IV lung cancer combined with diabetes was significantly improved with metformin. Scholars at the European Institute of Oncology found that metformin and fasting can act synergistically to inhibit tumor growth in mice . Marsha rich rosner of the University of Chicago reported in Nature that triple-negative breast cancer treated with metformin alone, or inhibiting the BACH1 protein alone had no significant anticancer effect. However, when tumor-bearing mice were treated with a combination of heme and metformin, tumor growth was significantly inhibited! Not only breast cancer, but also lung cancer, kidney cancer, uterine cancer, prostate cancer, and acute myeloid leukemia, this treatment strategy may be effective for a variety of cancers. Mingqi Hong of the MD Anderson Cancer Center found that Metformin can cause degradation of PD-L1 expressed by cancer cells to prevent them from "escaping the search" of the immune system, and that this can lead to a significant reduction in tumor growth. "This combination therapy has been approved by the FDA for clinical trials.
Patients with higher gut bacterial diversity had longer median progression-free survival, and another study from the University of Chicago found that melanoma growth was different in mice modeled for melanoma depending on the bacterial flora colonizing their intestines. The presence of specific species of the genus Bifidobacterium (e.g., Bifidobacterium shortum, Bifidobacterium longum, and Bifidobacterium adolescentum) in the intestinal tract of mice enhances the anticancer effect of the PDL1 antibody by increasing the number of CD8+ T cells. The abundance of an Akkermansia muciniphila (Akk bacteria) colony in the body, which contributes to fat burning and modifies blood glucose levels and is expected to contribute to the improvement of the metabolic profile of obese and diabetic patients, was low, and on the contrary, patients in the presence of this colony experienced symptomatic relief after immunotherapy. It may be related to the fact that microorganisms such as Akk bacteria and Enterococcus hirae induce dendritic cells to release the inflammatory mediator interleukin-12 (IL-12), thereby recruiting more CD4+ T cells to concentrate around the tumor, and the concentration of T cells enhances the body's anti-tumor ability.
Galectin-3 overexpression promotes tumor transformation and maintains a transformed phenotype, and enhances adhesion of tumor cells to the extracellular matrix and increases metastatic spread. 90% of patients with strong positive expression of galectin-3 experience rapid progression and deterioration early in the course of the disease (Spider diagram - red curve), whereas negatively expressing patients experience disease remission (Spider diagram - green color). This study suggests that galectin-3 may be a biomarker worth exploring beyond PD-L1 expression. Studies targeting the galectin-3 pathway are ongoing. gcs-100, derived from citrus pectin, removes the protective galectin-3 from the exterior of the cell. once galectin-3 is removed, chemotherapeutic agents are able to effectively target the lymphoma cells, leading to apoptotic cell death. The results suggest that small molecules of citrus pectin may be potential blockers of cancer cell interactions, which are carried out by carbohydrate-binding proteins on the cell surface.
Studies have found that tumors that fail conventional immunotherapy, with increasing interstitial potassium ions can severely damage T-cell metabolism. Studies have found that tumors that fail conventional immunotherapy, with increasing interstitial potassium ions can severely damage T-cell metabolism, interfering with the cellular uptake of nutrients from outside the cell, which is equivalent to leaving these cells in a starvation state. The lack of energy material T cells will inevitably lead to a decline in function, anti-tumor immune function naturally can not be achieved. On the other hand, it was also found that at high concentrations of K+ can affect T cell epigenetic modification, allowing T cells to restore stemness. Potassium ions inhibit the activity of immune T cells in the tumor microenvironment. Hydroxycitric acid inhibits acylATP citrate lyase, similar to lowering the concentration of K ions in the tumor microenvironment and increasing the PD1 effect. Hydroxycitric acid is a derivative of citric acid, which is widely found in tropical rainforest plants such as Garcinia Cambogia and Roselle.
Cancer cells release biological "drones", small vesicles called exosomes, which circulate in the bloodstream and carry the PD-L1 protein, causing T-cell "fatigue" before they can reach the cancer cells to do battle. Levels of exosomal PD-L1 can indicate the level of T-cell activation by immune checkpoint inhibitors. Circulating levels of exosomal PD-L1 are positively correlated with levels of IFN-γ and change over the course of anti-PD-1 therapy.