The Age of Cyclic Dinucleotide Vaccine Adjuvants

As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance

Improving the functional avidity of effector T cells is critical in overcoming inhibitory factors within the tumor microenvironment and eliciting tumor regression. We have found that Cish, a member of the suppressor of cytokine signaling (SOCS) family, is induced by TCR stimulation in CD8+ T cells and inhibits their functional avidity against tumors. Genetic deletion of Cish in CD8+ T cells enhances their expansion, functional avidity, and cytokine polyfunctionality, resulting in pronounced and durable regression of established tumors. Although Cish is commonly thought to block STAT5 activation, we found that the primary molecular basis of Cish suppression is through inhibition of TCR signaling. Cish physically interacts with the TCR intermediate PLC-γ1, targeting it for proteasomal degradation after TCR stimulation. These findings establish a novel targetable interaction that regulates the functional avidity of tumor-specific CD8+ T cells and can be manipulated to improve adoptive cancer immunotherapy.

Unique potential of 4-1BB agonist antibody to promote durable regression of HPV+ tumors when combined with an E6/E7 peptide vaccine

Antibody modulation of T-cell coinhibitory (e.g., CTLA-4) or costimulatory (e.g., 4-1BB) receptors promotes clinical responses to a variety of cancers. Therapeutic cancer vaccination, in contrast, has produced limited clinical benefit and no curative therapies. The E6 and E7 oncoproteins of human papilloma virus (HPV) drive the majority of genital cancers, and many oropharyngeal tumors. We discovered 15–19 amino acid peptides from HPV-16 E6/E7 for which induction of T-cell immunity correlates with disease-free survival in patients treated for high-grade cervical neoplasia. We report here that intranasal vaccination with these peptides and the adjuvant alpha-galactosylceramide elicits systemic and mucosal T-cell responses leading to reduced HPV+ TC-1 tumor growth and prolonged survival in mice. We hypothesized that the inability of these T cells to fully reject established tumors resulted from suppression in the tumor microenvironment which could be ameliorated through checkpoint modulation. Combining this E6/E7 peptide vaccine with checkpoint blockade produced only modest benefit; however, coadministration with a 4-1BB agonist antibody promoted durable regression of established genital TC-1 tumors. Relative to other therapies tested, this combination of vaccine and α4-1BB promoted the highest CD8+ versus regulatory FoxP3+ T-cell ratios, elicited 2- to 5-fold higher infiltration by E7-specific CTL, and evoked higher densities of highly cytotoxic TcEO (T cytotoxic Eomesodermin) CD8 (>70-fold) and ThEO (T helper Eomesodermin) CD4 (>17-fold) T cells. These findings have immediate clinical relevance both in terms of the direct clinical utility of the vaccine studied and in illustrating the potential of 4-1BB antibody to convert therapeutic E6/E7 vaccines already in clinical trials into curative therapies.

Chlamydia psittaci (Cp)-eradicating therapy with doxycycline is an active treatment against ocular adnexa MALT lymphoma (OAML): Final results of a multicentre prospective trial

7559 Background: An association between OAML and Cp infection has been reported. Preliminary data suggest that patients (pts) with Cp-related OAML could achieve lymphoma regression after eradicating therapy with doxycycline, while data on the activity of this strategy in Cp-negative OAML are not available. Methods: In this multicentre prospective trial, 27 consecutive pts with OAML and measurable disease, at diagnosis (n = 15) or relapse, were treated with doxycycline 100 mg, bid orally, for 3 weeks. Objective response was the primary endpoint. The presence of Cp DNA in lymphoma samples was evaluated by TETR-PCR. Results: Tolerability was excellent in all pts but one. At a median follow-up of 13 mo. (range 3–45), response was complete (CR) in 6 pts and partial in 7 (ORR = 48%; 95% CI:30%-66%); three pts had a response <50%, 9 had stable disease (3–13 mo.), two had progressive disease. Response was slow; 5 pts achieved the best response only after one year of follow-up (median time to the best response: 6 mo.). TETR-PCR resulted positive in 11 (41%) pts and negative in 16. Lymphoma regression was observed in both PCR-positive and -negative pts (64% vs. 38%; p = 0.25), with a CR rate of 36% and 13% (p = 0.18), respectively. Response rate was similar between pts with conjunctival and intra-orbital lymphomas (43% vs. 54%, p = 0.71). The three pts with regional lymphadenopathies and three of the 5 pts with bilateral OAL achieved objective response (4 CRs), which lasted 3+, 13+, 16+, 22+, 26+, and 37 mo. In relapsed pts, objective response was observed in 3 of 5 previously irradiated pts and in 5 of 7 non-irradiated pts (p = 0.99). Twenty pts are failure-free, with a 2-yr FFS of 66±12%. Conclusions: Doxycycline is a fast, cheap and safe therapy, able to induce durable regression in 64% of Cp-related OAML. This antibiotic is a valid alternative against OAML, even in pts with multiple failures, involving previously irradiated areas or regional lymph nodes. We report for the first time responses also in PCR-negative OAML; this finding stimulates the development of more sensitive and specific methods for Cp detection and the study of potential associations with other infectious agents responsive to doxycycline. No significant financial relationships to disclose.