ORR up to 59%! PD-1 antibody combined with new antigen vaccine IB phase trial data.

Wen: White Dew immunosuppressants (ICI) have revolutionized the treatment of cancer patients over the past 10 years.
PD-1 and PD-L1 antibodies show significant anti-tumor activity in a variety of cancers.
, however, despite the success of PD-1 antibody therapy in a variety of tumor types, only a small percentage of patients have benefited from long-term clinical benefits from treatment.
, scientists have shown great interest in conducting joint therapist treatments to improve the efficacy of immunosuppression.
new antigen originates from mutations in cancer cells and is an important target for T-cell-mediated immunity.
high levels of new antigen load in tumors were associated with good clinical response and progress-free lifetime (PFS) improvement in patients with multiple types of tumors treated with anti-PD-1.
recently, BioNTech US's Lakshmi Srinivasan and Dana Faber Cancer Research Institute's Patrick A. Ott team worked together to make a new breakthrough.
Their latest study presents the results of the first open clinical trial (NCT02897765) of the personalized new antigen vaccine combined with PD-1 blocking therapy for patients with advanced melanoma, non-small cell lung cancer, or bladder cancer, which supports the program's feasibility, safety, and immunogenicity for patients with advanced solid tumors.
study was published in Cell on October 15.
Photo Source: Cell Specifically, the study is open to patients with non-removable or metastatic melanoma, smoking-related non-small cell lung cancer, and bladder urethra cancer, and is being recruited at nine major cancer centers in the United States.
major research endpoints include assessment of safety, objective response rate (ORR), progress-free lifetime (PFS), and comprehensive immunologic analysis of blood and tumors.
In order to produce the personalized new antigen vaccine NEO-PV-01, the researchers first identified tumor mutations by sequencing whole exoscopes and RNA in a fixed tumor sample in each patient and compared these mutation information to normal cells in the blood outlined in the vaccine manufacturing program (Figure A below).
then use biometric algorithms to select high-quality new antigen countersetotes encoded by somatic cell mutations and prioritize new tables.
NEO-PV-01 vaccine manufacturing, clinical research design and patient giving (Photo: Cell) Each new antigen vaccine consists of 20 unique peptides, between 14 and 35 amino acids, mixed with the admixation poly-ICLC.
the production of the vaccine, patients were treated with Navuliyu monoantigen for 12 weeks.
NEO-PV-01 injections from week 12, 5 Priming vaccinations and 2 intensive vaccinations were performed in 3 months to form a complete NEO-PV-01 course of treatment.
continue to use Navuliyu monoantigen for two periods after vaccination and vaccination (figure B above).
November 2016 to August 2018, a total of 82 patients with at least one dose of Navuliyu monoma were registered, of which 60 patients (27 cases of melanoma, 18 cases of non-small cell lung cancer, 15 cases of bladder cancer) were vaccinated.
In terms of safety and tolerance of NEO-PV-01 and Navuliyu monoantigen, the most common adverse reactions in vaccinated patients were injection site reactions and influenza-like diseases (52% and 35%, respectively).
reaction at the injection site usually manifests it as a brief local fever and erythema.
all cases were mild except for one patient with stage 2 erythema at the injection site (standard level 1, a common term for adverse drug events).
adverse events associated with the injection site did not cause any patient NEO-PV-01 dose to be interrupted or stopped.
treatment-related events, only 2 cases showed side effects of R3 severity, of which 1 was hypokalemia and rash, and no serious adverse events associated with treatment were observed.
objective mitigation rate (ORR, version 1.1 of the efficacy evaluation criteria for solid tumors), PFS, and total lifetime (OS) were analyzed for follow-up data for at least 12 months up to August 2019.
among vaccinated patients (N-60), ORR (95% confidence interval (CI)) and 39% of patients with melanoma, non-small cell lung cancer and bladder cancer were 59% (39%-78%), respectively (39%-78%) 17%-64%) and 27% (8%-55%); NE) and 5.8 months (2.8, 12.7); The one-year total survival rate was 96% (76%-99%), 83% (57-94%) and 67% (38-85%), respectively.
in melanoma and non-small cell lung cancer, the mid-OS for vaccinated patients was not reached, while the medium OS for bladder cancer was 20.7 months (4.8, NE).
data have a good advantage over the historical data of anti-PD-1 monodring therapy.
ITT set - intention-to-treat set, refers to 82 patient groups that received at least 1 dose of PD-1 antibody (Photo: Cell) Further studies have shown that tumor mutation load and surface quality are important determinants of the response to the combined anti-PD-1 treatment of the new antigen vaccine.
In addition, NEO-PV-01 combined PD-1 inhibitors induce specific and persistent T-cell responses to new antigen mesotytes in all tumor queues, and new antigen vaccine-specific T-cells have potential cytotoxicity that migrates to tumors and kills cancer cells.
taking into account the detection of memory and potential cytotoxic T-cells in tumors, the researchers concluded that new antigen-specific T-cells kill tumor cells by releasing additional metastates, resulting in a broader new antigen-specific immune response.
this phenomenon, known as surface diffusion, has previously been reported to be important for expanding T-cell responses to vaccines.
subsequent evaluation experiments showed that the degree of table diffusion response was associated with longer PFS in all three tumor queues.
results show that new antigen-induced T cells produced by NEO-PV-01 not only transfer to the tumor, but also lead to the release of additional new antigens by killing tumor cells, which become additional T-cell targets.
diffusion of the table can be a process of self-amplification.
this suggests a broad immune response to the expression of new antigens, perhaps only a subset of the new antigens expressed on the tumor.
the production of the surface diffusion may help control tumor cells that do not express the new antigens of the trunk (truncal), and may therefore be a mechanism for controlling tumor heterogeneity.
, the researchers observed the main pathological response after NEO-PV-01 vaccination in the melanoma queue.
results showed a large number of tumors in pre-treatment (95%) and pre-vaccination (40%) biopsies.
, however, there was no evidence of residual live tumors in the five core biopsies obtained at the point in time after vaccination.
note that at the point in time before and after vaccination, the leaching of CD3-T cells in tumors increased (see figure below).
Photo Source: Cell additionally performed tumor biopsies at 3 points in time (before, during, and after vaccination) at the same anatomical site for 19 melanoma patients, and assessed the results of treatment-related pathological responses that showed that surface diffusion was associated with reduced tumor cells after vaccination.
In summary, the study demonstrates the feasibility and safety of this personalized antigen-based vaccine in association with PD-1 inhibitors to produce new antigen-specific CD4-plus and CD8-T cells, which exhibit memory esoteric, cytotoxic, mutation-specific and persistent, and can migrate to tumors to mediate tumor-specific immune killing.
addition, there is hope for future randomized studies using exo-blood and tumor biomarkers to select patients.
additional studies are necessary to better improve the program and determine whether the combination of personalized new antigen vaccines with PD-1 inhibitors can play a good role in cancer treatment.
: Patrick A. Ott et al. A Phase Ib Trial of National Neoantigen Therapy Plus Anti-PD-1 in Patients with Advanced Melanoma, Non-small Cell Lung Cancer, or Bladder Cancer. Cell (2020) Source: Medical Rubik's Cube Pro.