Oncology
Prostate Cancer
Immunotherapy Given Earlier in the Disease Course Improves Survival and Is Linked to Distinct Antibody Profiles
Overview
Clinical Study Title:
Response to nontargeted antigens may serve as a useful surrogate for the degree of immune activation.
Clinical Study Abstract:
- Background: Sip-T, an FDA-approved autologous immunotherapy for patients with asymptomatic or minimally symptomatic metastatic castration-resistant PC (mCRPC), 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. In sip-T–treated patients, antibody responses to PA2024/PAP (target antigens) and AgS (antibody responses to secondary [2°] antigens) correlate with improved OS. We assessed if a greater magnitude of AgS would be observed in an earlier PC disease stage when the immune system is more intact.
- Methods: Patient serum was from 1 non-metastatic, androgen-dependent PC (ADPC) sip-T trial (STAND, sip-T + androgen deprivation, NCT01431391) and 3 mCRPC sip-T trials (IMPACT, sip-T vs control, NCT00065442; STAMP, sip-T + abiraterone acetate, NCT01487863; STRIDE, sip-T + enzalutamide, NCT01981122). Using a Luminex assay, mean fold-change in IgG responses to target and 2° cancer-related antigens (PSA, LGALS3, LGALS8, ERAS, KRAS, KLK2) was evaluated from baseline to Week 6.
- Results: AgS was evaluated in 308 patients. The mean fold-change in IgG responses to target antigens was greater for ADPC vs mCRPC patients (P < .01). Moreover, the magnitude of IgG responses was greater for most 2° antigens in ADPC vs mCRPC patients (P < .05), except for PSA and KLK2 in ADPC vs STRIDE patients.
- Conclusions: The magnitude of antibody responses to target and 2° antigens was greater earlier in the PC disease course, consistent with increased antigen-presenting cell activation in ADPC vs mCRPC patients. Increased AgS likely reflects stronger sip-T–induced immune responses, previously associated with extended OS in mCRPC. Future research is warranted on the clinical benefit of sip-T earlier in the PC disease course and the potential impact of androgen suppression on the magnitude of AgS and outcomes.
Reference:
Fong L, Small EJ, Petrylak DP, et al. Antigen spread after sipuleucel-T: a cross-trial comparison of 4 sip-T clinical trials of patients with prostate cancer. J Clin Oncol. 2017;35(suppl 6S): Abstract 143.
Expert Commentary
William K. Oh, MD
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Sipuleucel-T has been approved in the United States since 2010 for men with asymptomatic or minimally symptomatic mCRPC. Patients and clinicians have often wondered whether this immune therapy might have greater benefit if used in earlier disease states, given that the immune system is less robust as patients develop progressive disease. Several trials were attempted in the neoadjuvant and rising prostate-specific antigen (PSA) settings but were nonconclusive. This pooled analysis gives some insight into the possibility that a surrogate for immunogenicity of vaccine therapy—namely, antigen spread (AgS)—may be greater in androgen-dependent prostate cancer compared with CRPC. Indeed, it makes sense that immunotherapy would have greater efficacy in patients with lower volume disease, and a post hoc analysis of IMPACT showed that the survival benefit was greatest in those treated with the lowest PSAs on study entry. The concept of AgS is also interesting with respect to immune activation, however. These data suggest that sipuleucel-T is inducing a specific immune response against not just prostatic acid phosphatase—the target antigen of sipuleucel-T—but also against other antigens expressed in prostate cancer. AgS in sipuleucel-T–treated patients compared with placebo-treated patients suggests that the antibody profiles are broader than a specific response to just one antigen. In summary, vaccine and immunotherapy approaches may be more valuable in patients treated early in their disease course, and AgS may be a surrogate of the degree of immune activation. |
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"These data suggest that sipuleucel-T is inducing a specific immune response against not just prostatic acid phosphatase—the target antigen of sipuleucel-T—but also against other antigens expressed in prostate cancer."
