Sipuleucel-T (sip-T)–induced lytic CD8+ T cell responses to target antigens in men with hormone-sensitive and castration-resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e23116-e23116
Author(s):  
Emmanuel S. Antonarakis ◽  
David I. Quinn ◽  
Adam S. Kibel ◽  
Daniel Peter Petrylak ◽  
Tuyen Vu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Castration Resistant ◽  
Hormone Sensitive

scholarly journals Pre-existing immune status associated with response to combination of sipuleucel-T and ipilimumab in patients with metastatic castration-resistant prostate cancer

2021 ◽  
Vol 9 (5) ◽  
pp. e002254
Author(s):  
Meenal Sinha ◽  
Li Zhang ◽  
Sumit Subudhi ◽  
Brandon Chen ◽  
Jaqueline Marquez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Clinical Response ◽  
T Cell Responses ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Castration Resistant ◽  
Clinical Responses

BackgroundSipuleucel-T is a US Food and Drug Administration-approved autologous cellular immunotherapy that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We examined whether administering ipilimumab after sipuleucel-T could modify immune and/or clinical responses to this treatment.MethodsA total of 50 patients with mCRPC were enrolled into a clinical trial (NCT01804465, ClinicalTrials.gov) where they received ipilimumab either immediately or delayed 3 weeks following completion of sipuleucel-T treatment. Blood was collected at various timepoints of the study. Luminex assay for anti-prostatic acid phosphatase (PAP) and anti-PA2024-specific serum immunoglobulin G (IgG) and ELISpot for interferon-γ (IFN-γ) production against PAP and PA2024 were used to assess antigen-specific B and T cell responses, respectively. Clinical response was defined as >30% reduction in serum prostate-specific antigen levels compared with pretreatment levels. The frequency and state of circulating immune cells were determined by mass cytometry by time-of-flight and statistical scaffold analysis.ResultsWe found the combination to be well tolerated with no unexpected adverse events occurring. The timing of ipilimumab did not significantly alter the rates of antigen-specific B and T cell responses, the primary endpoint of the clinical trial. Clinical responses were observed in 6 of 50 patients, with 3 having responses lasting longer than 3 months. The timing of ipilimumab did not significantly associate with clinical response or toxicity. The combination treatment did induce CD4 and CD8 T cell activation that was most pronounced with the immediate schedule. Lower frequencies of CTLA-4 positive circulating T cells, even prior to treatment, were associated with better clinical outcomes. Interestingly, these differences in CTLA-4 expression were associated with prior localized radiation therapy (RT) to the prostate or prostatic fossa. Prior radiation treatment was also associated with improved radiographic progression-free survival.ConclusionCombining CTLA-4 blockade with sipuleucel-T resulted in modest clinical activity. The timing of CTLA-4 blockade following sipuleucel-T did not alter antigen-specific responses. Clinical responses were associated with both lower baseline frequencies of CTLA-4 expressing T cells and a history of RT. Prior cancer therapy may therefore result in long-lasting immune changes that influence responsiveness to immunotherapy with sipuleucel-T and anti-CTLA-4.

Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer

2020 ◽  
Vol 12 (537) ◽  
pp. eaaz3577 ◽  
Author(s):  
Sumit K. Subudhi ◽  
Luis Vence ◽  
Hao Zhao ◽  
Jorge Blando ◽  
Shalini S. Yadav ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
T Cell Responses ◽  
Gene Signature ◽  
Immune Checkpoint Blockade ◽  
Castration Resistant Prostate Cancer ◽  
Cell Responses ◽  
Immune Correlates ◽  
Castration Resistant ◽  
Clinical Responses

Tumors with high mutational burden (TMB) tend to be responsive to immune checkpoint blockade (ICB) because there are neoantigens available for targeting by reinvigorated T cells, whereas those with low TMB demonstrate limited clinical responses. To determine whether antigen-specific T cell responses can be elicited after treatment with ICB in cancers that have a low TMB, we conducted a clinical trial with ipilimumab in 30 patients with metastatic castration-resistant prostate cancer. We identified two distinct cohorts by survival and progression times: “favorable” (n = 9) and “unfavorable” (n = 10). Patients in the favorable cohort had high intratumoral CD8 T cell density and IFN-γ response gene signature and/or antigen-specific T cell responses. Two patients with a relatively low TMB had T cell responses against unique neoantigens. Moreover, six of nine patients in the favorable group are still alive at the time of analysis, with survival ranging from 33 to 54 months after treatment. All 10 patients in the unfavorable cohort have succumbed to their disease and had survival ranging from 0.6 to 10.3 months. Collectively, our data indicate that immunological correlates associated with effector T cell responses are observed in patients with metastatic prostate cancer who benefit from ICB.

Randomized phase II study evaluating the addition of pembrolizumab to radium-223 in metastatic castration-resistant prostate cancer.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 98-98
Author(s):  
Atish Dipankar Choudhury ◽  
Lucia Kwak ◽  
Alexander Cheung ◽  
Abhishek Tripathi ◽  
Amanda Fredericks Pace ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Cd8 T Cell ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Cell Infiltrate ◽  
Castration Resistant ◽  
Radium 223 ◽  
Pathologic Fractures ◽  
Bone Biopsies

98 Background: Treatment (tx) options for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) to bone are limited. Radium-223 (R223) has demonstrated overall survival (OS) benefit, but objective clinical responses to R223 or the anti-PD1 checkpoint inhibitor (CPI) pembrolizumab (pem) are infrequent. As R223 may increase immunogenicity of mCRPC to bone and increase activity of CPI, we undertook a Phase 2 study to assess safety of the combination and differences in immune cell infiltrate in bone biopsies (bx) and preliminary clinical activity of R223 + pem vs. R223 alone. Methods: Eligibility required mCRPC to bone with no visceral metastases (mets) or lymph nodes > 2 cm, ECOG PS 0 or 1, Hgb ≥ 9 g/dL, and no prior R223 or CPI. Pts underwent bone bx at screening and at 8 wks. Pts were stratified by alkaline phosphatase ≥220 vs. < 220 U/L and high vs. low volume bony mets (CHAARTED criteria) and randomized 2:1 to receive R223 55 kBq/kg q4wks + pem 200 mg q3wks (Arm A) or R223 55 kBq/kg q4wks alone (Arm B). If restaging after 3 doses R223 showed at least stable disease, pts in Arm A continued pem alone until progressive disease (PD). Upon PD, R223 was resumed if no new visceral mets. Pts continued tx until clinical/radiologic PD, unacceptable toxicity or completion of 6 R223 doses. The primary endpoint was difference in CD4+ and CD8+ T-cell infiltrate in 8 wk vs. baseline bx; secondary endpoints were safety/tolerability, radiographic progression-free survival (rPFS) and OS. Exploratory endpoints included PSA response and rate of symptomatic skeletal events (SSEs). Results: Of 45 pts enrolled, 42 received study tx (29 Arm A, 13 Arm B) and were eligible for analysis. 21 pts in Arm A and 5 in Arm B had evaluable paired bone bx. Median fold-change of proportion of CD4+ T-cells/total cell count from baseline to 8 wks was 0.90 (range 0.0-26.6) in Arm A and 0.40 (0.0-13.0) in Arm B (P = 0.87); for CD8+ cells, median 0.67 (0.0-40.4) in Arm A and 0.40 (0.1-28.8) in Arm B (P = 0.77). Grade 3 treatment-related non-hematologic adverse events (AEs) occurred in 3 pts (10%) in Arm A (pneumonitis, diarrhea, AST increased); none in Arm B. Median rPFS was 6.7 mo (95% CI 2.7-11.0 mo) in Arm A and 5.7 mo (2.6-NR) in Arm B. Median OS was 16.9 mo (12.7-NR) in Arm A and 16.0 mo (9.0-NR) in Arm B. 3 pts (10%) in Arm A and 0 in Arm B had PSA reduction of ≥ 50%. SSE rate was 38% in Arm A and 54% in Arm B, with pathologic fractures in 0% of pts in Arm A and 23% in Arm B. Conclusions: In the 62% of treated pts with evaluable paired bx at baseline and after 8 wks, there was no evidence of increased CD4+ or CD8+ T-cell infiltration with R223 + pem. Additional biomarker analyses will be presented. This study revealed that R233 + pem did not result in unexpected AEs, but did not lead to prolonged rPFS or OS compared to R223 alone to support this two-drug combination in a biomarker-unselected population in this setting. Clinical trial information: NCT03093428.

scholarly journals DNA fusion-gene vaccination in patients with prostate cancer induces high-frequency CD8+ T-cell responses and increases PSA doubling time

2012 ◽  
Vol 61 (11) ◽  
pp. 2161-2170 ◽  
Author(s):  
Lindsey Chudley ◽  
Katy McCann ◽  
Ann Mander ◽  
Torunn Tjelle ◽  
Juan Campos-Perez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
High Frequency ◽  
Doubling Time ◽  
Fusion Gene ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Psa Doubling Time ◽  
Gene Vaccination

Sipuleucel-T (sip-T)–induced proliferative CD8+ T-cell responses to immunizing and secondary antigens.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 165-165 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
David I. Quinn ◽  
Adam S. Kibel ◽  
Daniel Peter Petrylak ◽  
Nancy N. Chang ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Antibody Responses ◽  
Castration Resistant Prostate Cancer ◽  
Peripheral Blood Mononuclear ◽  
Cell Responses

165 Background: Sip-T is an FDA-approved autologous immunotherapy for patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Sip-T is manufactured from peripheral blood mononuclear cells cultured with PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage-colony stimulating factor (GM-CSF). In sip-T–treated pts, T cell and antibody responses to PA2024 or PAP as well as antibody responses to secondary antigens (i.e., antigen spread) correlate with improved overall survival. To explore the biology of this relationship, we further characterized the T cell subpopulations involved in the cellular immune responses to sip-T. Methods: In vitro proliferative CD8+ (cytotoxic T lymphocyte) and CD4+ (T helper) T cell responses to PA2024 and PAP as well as to secondary antigens (PSA, LGALS3, and KRAS) were evaluated using flow cytometry on pt samples from two sip-T–containing clinical trials (STAND [NCT01431391] and STRIDE [NCT01981122]). Results: PA2024-specific CD8+ and CD4+ responses were observed beginning 2 weeks after the first sip-T infusion through week 26 in most evaluable pts. CD8+ and CD4+ responses to PAP were also observed, although the magnitude of this response (to a self-antigen) was smaller when compared with PA2024 responses. Most pts with CD8+ responses to PA2024 also had a CD4+ response, which occurred more frequently than CD8+ responses. Both CD8+ and CD4+ responses to secondary antigens were amplified after sip-T, and these CD8+ proliferative responses to secondary antigens were greater in magnitude compared with CD4+ responses. Conclusions: Here,we report the first evidence of antigen-specific CD8+ responses in pts receiving sip-T, indicating CD8+ T cell involvement in sip-T–mediated immune responses that occur in concert with the expected CD4+ T cell responses to soluble antigens (i.e., PA2024). These CD8+ responses were durable, lasting up to 26 weeks post–sip-T treatment. Importantly, responses to secondary antigens and in particular, CD8+ responses, were also amplified after sip-T treatment, suggesting that antigen spread could be resulting from sip-T–mediated tumor cell lysis. Clinical trial information: NCT01431391 and NCT01981122.

scholarly journals Phase I study of a multitargeted recombinant Ad5 PSA/MUC-1/brachyury-based immunotherapy vaccine in patients with metastatic castration-resistant prostate cancer (mCRPC)

2021 ◽  
Vol 9 (3) ◽  
pp. e002374
Author(s):  
Marijo Bilusic ◽  
Sheri McMahon ◽  
Ravi A Madan ◽  
Fatima Karzai ◽  
Yo-Ting Tsai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiation Therapy ◽  
T Cell ◽  
Partial Response ◽  
Castration Resistant Prostate Cancer ◽  
Vaccine Platform ◽  
Cell Responses ◽  
Castration Resistant ◽  
Palliative Radiation Therapy ◽  
Recommended Phase Ii Dose

BackgroundAntitumor vaccines targeting tumor-associated antigens (TAAs) can generate antitumor immune response. A novel vaccine platform using adenovirus 5 (Ad5) vectors [E1–, E2b–] targeting three TAAs—prostate-specific antigen (PSA), brachyury, and MUC-1—has been developed. Both brachyury and the C-terminus of MUC-1 are overexpressed in metastatic castration-resistant prostate cancer (mCRPC) and have been shown to play an important role in resistance to chemotherapy, epithelial–mesenchymal transition, and metastasis. The transgenes for PSA, brachyury, and MUC-1 all contain epitope modifications for the expression of CD8+ T-cell enhancer agonist epitopes. We report here the first-in-human trial of this vaccine platform.MethodsPatients with mCRPC were given concurrently three vaccines targeting PSA, brachyury, and MUC-1 at 5×1011 viral particles (VP) each, subcutaneously every 3 weeks for a maximum of three doses (dose de-escalation cohort), followed by a booster vaccine every 8 weeks for 1 year (dose-expansion cohort only). The primary objective was to determine the safety and the recommended phase II dose. Immune assays and clinical responses were evaluated.ResultsEighteen patients with mCRPC were enrolled between July 2018 and September 2019 and received at least one vaccination. Median PSA was 25.58 ng/mL (range, 0.65–1006 ng/mL). The vaccine was tolerable and safe, and no grade >3 treatment-related adverse events or dose-limiting toxicities (DLTs) were observed. One patient had a partial response, while five patients had confirmed PSA decline and five had stable disease for >6 months. Median progression-free survival was 22 weeks (95% CI: 19.1 to 34). Seventeen (100%) of 17 patients mounted T-cell responses to at least one TAA, whereras 8 (47%) of 17 patients mounted immune responses to all three TAAs. Multifunctional T-cell responses to PSA, MUC-1, and brachyury were also detected after vaccination in the majority of the patients.ConclusionsAd5 PSA/MUC-1/brachyury vaccine is well tolerated. The primary end points were met and there were no DLTs. The recommended phase II dose is 5×1011 VP. The vaccine demonstrated clinical activity, including one partial response and confirmed PSA responses in five patients. Three patients with prolonged PSA responses received palliative radiation therapy. Further research is needed to evaluate the clinical benefit and immunogenicity of this vaccine in combination with other immuno-oncology agents and/or palliative radiation therapy.Trial registration numberNCT03481816.

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