A phase 1b study of personalized neoantigen vaccine plus pembrolizumab in adults with advanced cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2615-2615
Author(s):  
Aaron Miller ◽  
Zeynep Kosaloglu-Yalcin ◽  
Luise Westernberg ◽  
Leslie Montero ◽  
Milad Bahmanof ◽  
...  
Keyword(s):  
T Cell ◽  
Injection Site ◽  
Cell Function ◽  
Injection Site Reaction ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Patient Specific ◽  
Clinical Activity ◽  
Site Reaction ◽  
Cell Responses

2615 Background: Neoantigens (NeoAg) are key targets for personalized immunotherapy but efficient methods for their systematic identification and therapeutic targeting remain elusive. We developed a methodology to reliably identify and verify somatic alteration-derived neoantigens based on natural T cell responses against them which formed the basis of an individualized therapeutic vaccine strategy. Methods: This is a phase Ib study to assess the immunogenicity, safety and early clinical activity of personalized synthetic long peptides (PSLP) cancer vaccines in combination with pembrolizumab for patients with treatment refractory metastatic solid tumors or PSLP vaccine alone as an adjuvant treatment with patients with no evidence of disease (NED) that incorporates patient-specific NeoAg identified by an HLA-agnostic, functional T-cell assay (see table). Results: At the time of data cutoff, a total of 5 patients had been treated on ARM-A, 5 patients on ARM-C and 2 patients on ARM-D. AES possibly attributed to personalized vaccine (PSLP), or pembrolizumab, or both include: Grade 1: Arthralgia (1); Diarrhea (1); Fever (4); Fatigue (7); Generalized muscle weakness (1); Headache (2); Nausea (1); Confusion (1); Injection site reaction (5); Rash maculo-papular (3); Flu like symptoms (5); Myalgia (1); and Grade 2: Diarrhea (1); Fatigue (1); Hyperhidrosis (1); Hypothyroidism (1); Injection site reaction (1); Proteinuria (1); Renal and Urinary – other (1); and Grade 3: Colitis (1). For the 9 patients with at least 1 radiographic assessment at the time of analysis 6 had a best response of stable disease (SD) and 3 had progressive disease (PD). Immune monitoring of peripheral blood specimens consistently demonstrated that NeoAg-specific T cell responses were enhanced following administration of PSLP vaccine. On-treatment biopsies demonstrated immune-editing with the variant allele frequency of targeted mutations decreasing following administration of the PSLP vaccine. Conclusions: Taken together, these data meet the trial primary endpoint by demonstrating PSLP vaccines targeting NeoAg identified using the HLA-agnostic pipeline augment effector T cell function against these targets. Clinical trial information: NCT02287428. [Table: see text]

GEN-009, a neoantigen vaccine containing ATLAS selected neoantigens, to generate broad sustained immunity against immunogenic tumor mutations and avoid inhibitory peptides.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3107-3107 ◽  
Author(s):  
Roger B. Cohen ◽  
Przemyslaw Twardowski ◽  
Melissa Lynne Johnson ◽  
Maura L. Gillison ◽  
Mark N. Stein ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Progression ◽  
Ex Vivo ◽  
Phase 1 ◽  
T Cell Responses ◽  
Patient Specific ◽  
Clinical Activity ◽  
Tumor Type ◽  
Inhibitory Peptides ◽  
Cell Responses

3107 Background: Tumor-specific neoantigens provide personalized targets for immunotherapy. Vaccines against epitopes predicted by in silico approaches very rarely induce CD4+ and CD8+ ex vivo T cell responses regardless of formulation. ATLAS selects neoantigens for vaccine inclusion using ex vivo screening of all patient-specific mutations to identify pre-existing CD4+ or CD8+ T cell responses and to exclude Inhibigens, which are inhibitory peptides that suppress immunity and accelerate tumor progression. The Inhibigen burden correlates with patient outcomes in observational studies and rapid tumor progression in mouse models. Methods: GEN-009-101 is a phase 1/2a study testing safety, immunogenicity and clinical activity in immune responsive tumors. After next-generation tumor sequencing and ATLAS testing of autologous leukocytes, up to 20 stimulatory synthetic long peptides adjuvanted with poly-ICLC comprise each personalized vaccine. Eight vaccinated patients have been followed for sustained immunological responses and clinical outcomes. Results: The 40 doses given across patients have induced only mild local discomfort and no DLT. Vaccination has generated immune responses against 99% of administered peptides, with both CD8+ and CD4+ responses in ex vivo fluorospot assays. To date, no patients have developed recurrent disease. Broad immunity develops as early as Day 29 and is sustained for over 12 months. Immune response against individual peptides is correlated with peptide concentration (OR = 1.26, p≤0.0001) but not with other classifiers such as GRAVY index (Grand Average of Hydropathy), tumor type, injection site or sex. The Inhibigen burden prior to treatment again correlates with disease progression. Conclusions: GEN-009 identifies tumor specific immune targets from the individual patient’s tumor mutagens. Initial clinical data show that ATLAS antigen selection may be critical to the induction of broad, rapid and sustained immunity against tumor specific neoantigens. Clinical vaccination with PD-1 blockade is in process. Clinical trial information: NCT03633110 . [Table: see text]

scholarly journals 248 Empiric profiling of peripheral T cell recall responses to tumor mutanomes versus in silico predictions in NSCLC patients undergoing pembrolizumab treatment ± chemotherapy

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A268-A268
Author(s):  
Madison Milaszewski ◽  
James Loizeaux ◽  
Emily Tjon ◽  
Crystal Cabral ◽  
Tulin Dadali ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
In Silico ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Patient Specific ◽  
In Silico Prediction ◽  
Cell Responses ◽  
In Silico Predictions

BackgroundEffective immune checkpoint blockade (ICB) treatment is dependent on T-cell recognition of patient-specific mutations (neoantigens). Empirical identification of neoantigens ex vivo has revealed shortcomings of in silico predictions.1 To better understand the impact of ICB treatment on T cell responses and differences between in silico and in vitro methods, neoantigen-specific T cell responses were evaluated in patients with non-small cell lung cancer undergoing first-line therapy with pembrolizumab ± chemotherapy.MethodsTumor and whole blood samples were collected from 14 patients prior to and after immunotherapy; seven each in monotherapy and combination therapy cohorts. The ex vivo ATLAS™ platform was used to profile neoantigen-specific T-cell responses. Patient-specific tumor mutations identified by next-generation sequencing (NGS) were expressed individually as ATLAS clones, processed patient-specific autologous antigen presenting cells, and presented to their T cells in vitro. ATLAS-verified antigens were compared with epitope predictions made using algorithms.ResultsOn average, 150 (range 37–339) non-synonymous mutations were identified. Pre-treatment, ATLAS identified T cell responses to a median of 15% (9–25%) of mutations, with nearly equal proportions of neoantigens (8%, 5–15%) and Inhibigens™, targets of suppressive T cell responses (8%, 3–13%). The combination therapy cohort had more confirmed neoantigens (46, 20–103) than the monotherapy cohort (7, 6–79). After treatment, the median ratio of CD4:CD8 T cells doubled in the monotherapy but not combination cohort (1.2 to 2.4 v. 1.6 to 1.3). Upon non-specific stimulation, T cells from patients on combination therapy expanded poorly relative to monotherapy (24 v. 65-fold, p = 0.014); no significant differences were observed pre-treatment (22 v. 18-fold, p = 0.1578). Post-treatment, the median number of CD8 neoantigens increased in the combination therapy cohort (11 to 15) but in monotherapy were mostly unchanged (6 to 7). Across timepoints, 36% of ATLAS-identified responses overlapped. In silico analysis resulted in 1,895 predicted epitopes among 961 total mutations; among those, 30% were confirmed with ATLAS, although nearly half were Inhibigens, which could not be predicted. Moreover, 50% of confirmed neoantigens were missed by in silico prediction.ConclusionsMonotherapy and combination therapy had differential effects on CD4:CD8 T cell ratios and their non-specific expansion. A greater proportion of neoantigens was identified than previously reported in studies employing in silico predictions prior to empirical verification.2 Overlap between confirmed antigens and in silico prediction was observed, but in silico prediction continued to have a large false negative rate and could not characterize Inhibigens.AcknowledgementsWe would like to acknowledge and thank the patients and their families for participating in this study.ReferencesLam H, McNeil LK, Starobinets H, DeVault VL, Cohen RB, Twardowski P, Johnson ML, Gillison ML, Stein MN, Vaishampayan UN, DeCillis AP, Foti JJ, Vemulapalli V, Tjon E, Ferber K, DeOliveira DB, Broom W, Agnihotri P, Jaffee EM, Wong KK, Drake CG, Carroll PM, Davis TA, Flechtner JB. An empirical antigen selection method identifies neoantigens that either elicit broad antitumor T-cell responses or drive tumor growth. Cancer Discov 2021;11(3):696–713. doi: 10.1158/2159- 8290.CD-20-0377. Epub 2021 January 27. PMID: 33504579. Rosenberg SA. Immersion in the search for effective cancer immunotherapies. Mol Med 27,63(2021). https://doi.org/10.1186/s10020-021-00321-3

scholarly journals Manipulation of Glucose Availability to Boost Cancer Immunotherapies

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2940
Author(s):  
Federica Marchesi ◽  
Debora Vignali ◽  
Beatrice Manini ◽  
Alessandra Rigamonti ◽  
Paolo Monti
Keyword(s):  
T Cell ◽  
Metabolic Regulation ◽  
Cell Function ◽  
Immune Cell ◽  
Deep Level ◽  
T Cell Responses ◽  
Cell Responses ◽  
T Cell Function ◽  
Cancer Tissues ◽  
Cancer Immunotherapies

The orchestration of T cell responses is intimately linked to the execution of metabolic processes, both in homeostasis and disease. In cancer tissues, metabolic alterations that characterize malignant transformation profoundly affect the composition of the immune microenvironment and the accomplishment of an effective anti-tumor response. The growing understanding of the metabolic regulation of immune cell function has shed light on the possibility to manipulate metabolic pathways as a strategy to improve T cell function in cancer. Among others, glucose metabolism through the glycolytic pathway is central in shaping T cell responses and emerges as an ideal target to improve cancer immunotherapy. However, metabolic manipulation requires a deep level of control over side-effects and development of biomarkers of response. Here, we summarize the metabolic control of T cell function and focus on the implications of metabolic manipulation for the design of immunotherapeutic strategies. Integrating our understanding of T cell function and metabolism will hopefully foster the forthcoming development of more effective immunotherapeutic strategies.

scholarly journals Helper T-Cell Responses and Clinical Activity of a Melanoma Vaccine With Multiple Peptides From MAGE and Melanocytic Differentiation Antigens

2008 ◽  
Vol 26 (30) ◽  
pp. 4973-4980 ◽  
Author(s):  
Craig L. Slingluff ◽  
Gina R. Petroni ◽  
Walter Olson ◽  
Andrea Czarkowski ◽  
William W. Grosh ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Peptide Vaccine ◽  
T Cell Responses ◽  
Delayed Type Hypersensitivity ◽  
Clinical Activity ◽  
Melanoma Vaccine ◽  
Cell Responses ◽  
Measurable Disease ◽  
Dose Levels

PurposeA phase I/II trial was performed to evaluate the safety and immunogenicity of a novel melanoma vaccine comprising six melanoma-associated peptides defined as antigenic targets for melanoma-reactive helper T cells. Source proteins for these peptides include MAGE proteins, MART-1/MelanA, gp100, and tyrosinase.Patients and MethodsThirty-nine patients with stage IIIB to IV melanoma were vaccinated with this six-peptide mixture weekly at three dose levels, with a preceding phase I dose escalation and subsequent random assignment among the dose levels. Helper T-lymphocyte responses were assessed by in vitro proliferation assay and delayed-type hypersensitivity skin testing. Patients with measurable disease were evaluated for objective clinical response by Response Evaluation Criteria in Solid Tumors.ResultsVaccination with the helper peptide vaccine was well tolerated. Proliferation assays revealed induction of T-cell responses to the melanoma helper peptides in 81% of patients. Among 17 patients with measurable disease, objective clinical responses were observed in two patients (12%), with response durations of 1 and 3.9+ years. Durable stable disease was observed in two additional patients for periods of 1.8 and 4.6+ years.ConclusionResults of this study support the safety and immunogenicity of a vaccine comprised of six melanoma helper peptides. There is also early evidence of clinical activity.

Dissection of anti-CTLA4-induced cytotoxic T-cell responses in melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9078-9078
Author(s):  
John B. A. G. Haanen ◽  
Pia Kvistborg ◽  
Daisy Philips ◽  
Sander Kelderman ◽  
Bianca Heemskerk ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Clinical Activity ◽  
Immune Reactivity ◽  
Cell Detection ◽  
Cell Reactivity ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses ◽  
T Cell Reactivity

9078 Background: There is strong evidence that melanoma-reactive T cells induced by immunotherapeutic interventions such as anti-CTLA4 therapy can exert clinically effects. However, there is very little information on how these therapies influence tumor-specific T cell responses. Furthermore, as the number of potential melanoma-associated antigens to which these responses can be directed is very high, classical strategies to map cytotoxic T cell reactivity do not suffice. Knowledge of such reactivities would be useful to design targeted strategies, selectively aiming to induce immune reactivity against these antigens. Methods: We have addressed these issues by designing MHC class I molecules occupied with UV-sensitive ‘conditional’ ligands, thereby allowing the production of very large collections of pMHC complexes for T cell detection. Secondly, we have developed a ‘combinatorial coding’ strategy that allows parallel detection of dozens of different T cell populations within a single sample. The combined use of MHC ligand exchange and combinatorial coding allows the high-throughput dissection of disease- and therapy-induced CTL immunity. We have used this platform to monitor immune reactivity against a panel of 145 melanoma-associated epitopes in patients receiving Ipilimumab treatment. Results: Comparison of PBMC samples from 32 melanoma patients pre- and post-therapy indicated a significant increase in the number of detectable melanoma-associated T cell responses (p=0.004). Furthermore, kinetic data on T cell responses during therapy suggests that this broadening generally occurs within weeks after start of therapy. The magnitude of melanoma-specific T cell responses that was detectable prior to start of therapy was not significantly altered (p=0.8). Conclusions: These results establish the pattern of melanoma-specific T-cell reactivity induced by anti-CTLA4 treatment and form a benchmark for evaluation of other immunotherapeutic interventions, like anti-PD1 treatment, that are currently undergoing clinical evaluation. Furthermore, our data suggests that the clinical activity of Ipilimumab may be mostly due to epitope spreading, rather than through enhancement of pre-existing immune activity.

scholarly journals T cell responses to tuberculin purified protein derivative in primary biliary cirrhosis: evidence for defective T cell function.

Gut ◽  
1997 ◽  
Vol 40 (2) ◽  
pp. 277-283 ◽  
Author(s):  
D E Jones ◽  
J M Palmer ◽  
M P Leon ◽  
S J Yeaman ◽  
M F Bassendine ◽  
...  
Keyword(s):  
T Cell ◽  
Primary Biliary Cirrhosis ◽  
Cell Function ◽  
T Cell Responses ◽  
Biliary Cirrhosis ◽  
Purified Protein Derivative ◽  
Cell Responses ◽  
T Cell Function

scholarly journals MHC Class I Presented T Cell Epitopes as Potential Antigens for Therapeutic Vaccine against HBV Chronic Infection

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Joseph D. Comber ◽  
Aykan Karabudak ◽  
Vivekananda Shetty ◽  
James S. Testa ◽  
Xiaofang Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Infection ◽  
Acute Infection ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Hbv Infection ◽  
Mhc I ◽  
Cell Responses ◽  
Cell Immunity

Approximately 370 million people worldwide are chronically infected with hepatitis B virus (HBV). Despite the success of the prophylactic HBV vaccine, no therapeutic vaccine or other immunotherapy modality is available for treatment of chronically infected individuals. Clearance of HBV depends on robust, sustained CD8+ T activity; however, the limited numbers of therapeutic vaccines tested have not induced such a response. Most of these vaccines have relied on peptide prediction algorithms to identify MHC-I epitopes or characterization of T cell responses during acute infection. Here, we took an immunoproteomic approach to characterize MHC-I restricted epitopes from cells chronically infected with HBV and therefore more likely to represent the true targets of CD8+ T cells during chronic infection. In this study, we identified eight novel MHC-I restricted epitopes derived from a broad range of HBV proteins that were capable of activating CD8+ T cells. Furthermore, five of the eight epitopes were able to bind HLA-A2 and A24 alleles and activated HBV specific T cell responses. These epitopes also have potential as new tools to characterize T cell immunity in chronic HBV infection and may serve as candidate antigens for a therapeutic vaccine against HBV infection.

scholarly journals HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

2015 ◽  
Vol 89 (18) ◽  
pp. 9189-9199 ◽  
Author(s):  
Cristina Andrés ◽  
Montserrat Plana ◽  
Alberto C. Guardo ◽  
Carmen Alvarez-Fernández ◽  
Nuria Climent ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Hiv 1

ABSTRACTHIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n= 24) (DC-HIV-1) or nonpulsed DCs (n= 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10to 1.9 copies/106CD4 T cells,P= 0.22) and did increase in controls (mean of 1.8 log10to 2.1 copies/106CD4 T cells,P= 0.02) (P= 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r[Pearson's correlation coefficient] = −0.69,P= 0.002, andr= −0.82,P< 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.)IMPORTANCEThere is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.

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