Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery

Abstract

Modulating the function of immune receptors with antibodies is ushering in a new era in cancer immunotherapy. With the notable exception of PD-1 blockade used as monotherapy, immune modulation can be associated with significant toxicities that are expected to escalate with the development of increasingly potent immune therapies. A general way to reduce toxicity is to target immune potentiating drugs to the tumor or immune cells of the patient. This Crossroads article discusses a new class of nucleic acid-based immune-modulatory drugs that are targeted to the tumor or to the immune system by conjugation to oligonucleotide aptamer ligands. Cell-free chemically synthesized short oligonucleotide aptamers represent a novel and emerging platform technology for generating ligands with desired specificity that offer exceptional versatility and feasibility in terms of development, manufacture, and conjugation to an oligonucleotide cargo. In proof-of-concept studies, aptamer ligands were used to target immune-modulatory siRNAs or aptamers to induce neoantigens in the tumor cells, limit costimulation to the tumor lesion, or enhance the persistence of vaccine-induced immunity. Using increasingly relevant murine models, the aptamer-targeted immune-modulatory drugs engendered protective antitumor immunity that was superior to that of current "gold-standard" therapies in terms of efficacy and lack of toxicity or reduced toxicity. To overcome immune exhaustion aptamer-targeted siRNA conjugates could be used to downregulate intracellular mediators of exhaustion that integrate signals from multiple inhibitory receptors. Recent advances in aptamer development and second-generation aptamer-drug conjugates suggest that we have only scratched the surface.

Aptamers as a Promising Therapeutic Tool for Cancer Immunotherapy

“…This new construct consisting of both the VEGF and the agonistic 4-1BB aptamers (represented in Figure 4b) showed less toxicity than the rest of the controls while obtaining the same therapeutic effect [87]. In fact, this therapeutic index widening was mirrored in a similar antitumor effect while reducing CD8+ T-cell hyperplasia as well as spleen, lymph node, lung, and liver weights [78,88]. These described works demonstrate the feasibility of the strategies based on targeting co-stimulation to the tumor site using aptamers.…”

Potentiating tumor immunity using aptamer-targeted RNAi to render CD8+ T cells resistant to TGFβ inhibition

“…39 Aptamers exhibit specificity and avidity comparable to or exceeding that of antibodies and can be generated against most targets. Recent studies, including studies from our laboratory reviewed in, 19 have demonstrated the feasibility and therapeutic potential of using aptamers as targeting ligands to deliver therapeutic siRNAs to tumor cells to eradicate tumors, 40 sensitize tumor cells to radiation therapy, 41 inhibit HIV replication, 42,43 and potentiate tumor immunity 20,44 Chemically synthesized aptamers represent a novel and emerging platform technology for drug delivery that offer potentially significant advantages in terms of manufacture, cost, regulatory approval process, straightforward conjugation of the targeting and therapeutic ligands (by hybridization between short complementary sequences engineered on both moieties), and lack or reduced immunogenicity. 39 To advance this approach to clinical testing human 4-1BB aptamer and SMAD4 siRNAs will have to be developed, the former being more challenging [17][18][19] and lack of toxicity, mainly lack of nucleic acid off-target effects, have to be demonstrated.…”

“…Aptamer ligands are used with increasing frequency to deliver therapeutic nucleic acid based cargo like siRNAs in vivo. [17][18][19] We have used aptamers to target immune modulatory siRNAs or aptamers to tumors or immune cells in mice, to express new antigens in the tumor lesions, 20 limit 4-1BB costimulation to tumors 21,22 or promote the differentiation of activated CD8 C T cells into long lasting memory cells. 23,24 This study describes the use of 4-1BB-Smad4 conjugate to potentiate vaccine-induced antitumor immune response in a murine breast cancer model.…”

Orchestrating a Symphony on a Single Conjugate: Aptamer Targeting, Gene Silencing, and Immunomodulation to Enhance Antitumor Response

“…8 Unlike antibodies, the entire production process can be carried out using chemical synthesis. 9 Additionally, aptamersiRNA conjugates may have an advantage over conventional siRNA introduction because of their processing by Dicer substrates.…”