Every tumor is a twisted reflection of the tissue from which it originates, studded with mutated and aberrantly expressed proteins. The immune system has the capacity to recognize these abnormalities, and researchers have long sought to devise therapeutic vaccines that spotlight such tumor-specific features in a manner that stimulates a robust counter-attack. Unfortunately, decades of work have yielded little clinical progress, with only one such vaccine approved to date in the United States: Dendreon Pharmaceuticals’ Provenge, which ultimately proved a commercial failure.1
It may therefore come as a surprise that many researchers in this space have a distinctly sunny outlook. “There’s a tremendous amount of promise for vaccine therapy right now,” says David E. Avigan, MD, a medical oncologist at Beth Israel Deaconess Medical Center. “I personally am very optimistic about where this work is going.” Some of this confidence results from insights accrued through progress in other areas of immunotherapy, such as chimeric antigen receptor (CAR) T cells and the various checkpoint inhibitor drugs. But much of it is also informed by lessons from past decades of cancer vaccine research, which have exposed the complexities associated with developing a broadly applicable strategy for marshaling a targeted antitumor response.
“Before, people were just vaccinating with one or two antigens at most—a ‘one-size-fits-all’ approach,” says Lana Kandalaft, PhD, an oncologist at Lausanne University Hospital in Switzerland. “But in ovarian cancer, for example, you have approximately 60 ‘private mutations’ per tumor that are specific to the particular tumor and patient.” Accordingly, many of today’s cancer vaccine strategies are personalized—tailored to the particular mutational profile of each patient’s tumor. These early efforts are beginning to show strong signs of promise in preclinical studies and early-phase clinical trials, although a great deal remains to be learned about how to design, formulate, and dose these vaccines for maximum clinical benefit.
Assembling a lineup
Many vaccine programs are centered around the identification of neoantigens—proteins that arise only in the aftermath of genomic mutation, and are therefore uniquely expressed by tumor cells. “The theory is that neoantigens might have a greater propensity to induce a T-cell response, because those targets are not truly ‘self’ proteins, where there might be tolerance because of mechanisms [that allow us] to avoid autoimmunity,” says Avigan. Buoyed by the rapidly plummeting costs and soaring quality of DNA sequencing, many labs are now combing through tumor genomes in search of such abnormal proteins.
Not all such proteins are immunogenic, however, and sophisticated algorithms are required to predict which neoantigens are most likely to be recognized and presented by host immune cells in a manner that drives a robust response. “We’ve characterized over a million proteins, and so our algorithms are really well-trained using neural networks,” explains Richard Gaynor, MD, president of R&D at Neon Therapeutics. “We’ve seen that we can induce immune responses broadly to at least 60% of selected vaccine peptides, and all patients develop an immune response.”
Neon’s flagship personalized vaccine program, NEO-PV-01, is built on research from co-founder Catherine J. Wu, MD, and her colleague Patrick A. Ott, MD, PhD, of the Dana-Farber Cancer Institute. In a study published in 2017,2 Wu, Ott, and colleagues administered individualized cocktails of tumor-specific neoantigen peptides to six melanoma patients within a few months of surgery. Four of the six remained disease-free after a median follow-up of 25 months. The remaining two patients suffered recurrance. In each of these two, recurrent disease was eliminated by concurrent administration of checkpoint inhibitors.
The vaccine formulation is relatively simple—a mixture of up to 20 peptides spanning 15–30 amino acids each, combined with an adjuvant. This makes it easy to manufacture different peptide epitopes from a given antigen to identify the best choice. Neon currently has multiple trials underway, and it recently presented preliminary data3 from a Phase I study in 55 patients with melanoma, lung, or bladder cancer.4 “We showed that it is safe and that you can get a broad immune response,” asserts Gaynor.
German immunotherapy company BioNTech is taking a slightly different approach, delivering combinations of neoantigens in the form of RNA molecules, which are injected directly into patients’ lymph nodes. In a pilot study from 2017,5 this approach elicited an immune response to the selected neoantigens in 13 melanoma patients who received the vaccine, with 8 remaining in remission after treatment. “In some patients, we had 5–7% of peripheral T cells recognizing tumor antigens,” recalls Ugur Sahin, MD, the company’s co-founder. BioNTech has multiple trials underway to further test this approach, including a large-scale Phase I study in which the company is collaborating with Genentech.6 “This trial,” notes Sahin, “aims to recruit over 500 patients with multiple indications.”
The bigger picture
A few dozen neoantigens can offer an effective “wanted poster” for tumor cells, but hand-picked epitopes still may not offer optimal immunogenicity. Furthermore, tumors are notorious for their heterogeneity and their capacity to evolve and shed molecular markers that render them vulnerable to therapy.
Accordingly, some researchers are hedging their bets and using whole tumor–derived preparations to achieve a more far-reaching immune response. “This way, we can vaccinate patients with everything that this tumor could present,” says Kandalaft. Her team has been breaking down tumor tissue collected from patients during surgery, and incubating the resulting lysates with dendritic cells (DCs) also harvested from the patient. DCs are responsible for presenting foreign antigens to T cells. Consequently, bathing DCs in a soup of cancer antigens can potentially initiate a far-reaching response against a wide range of target molecules in the tumor.
In a Phase I study published last spring,7 Kandalaft and colleagues used this approach to vaccinate 25 ovarian cancer patients, of whom 15 exhibited a clinical response. “Those patients who had immune responses also had an increase in their progression-free survival and overall survival,” she reports.
Avigan and colleagues have also opted for a whole tumor–targeted approach, but with a twist—performing a procedure in which patient-derived DCs are directly fused with tumor cells to produce immunologically active “hybridomas.”
“This DC-based system is really important because it provides critical immune costimulation,” insists Avigan. With collaborator Jacalyn Rosenblatt, MD, an associate professor of medicine at Harvard Medical School, Avigan has already tested this method in a variety of hematologic malignancies, obtaining particularly striking results in an elderly population of patients with acute myeloid leukemia.8
“Over 70% of those patients stayed in remission, and that correlated with a very profound and durable immune response,” he says, noting that this far exceeded his team’s expectations for this aged cohort. A much larger trial is now in the works,9 involving 17 cancer centers across the country.
Taking a less personalized approach, Ronald Levy, MD, professor and chief, division of oncology, Stanford University School of Medicine, believes that a well-designed “off the shelf” approach could also get the job done.10 Rather than immunizing with a single tumor antigen, Levy gives tumors a one-two punch. The first hit comes from a molecule called CpG, which stimulates local immunity at the tumor but also forces cancer cells to express a protein called OX40. The second hit comes from an antibody drug targeting OX40.
This approach selectively killed affected cells and generated a far-reaching immune response to antigens released from dying tumor cells; it worked against a wide range of tumors in mice; and it efficiently eliminated growths that originated from a primary tumor and had migrated elsewhere in the body.
“The immune response that we’re triggering is very specific for the antigens in the tumor that we’re injecting,” says Levy, who now has a trial underway to test this strategy in lymphoma patients.11
Only the beginning
Despite the encouraging progress in this field, Levy advises caution: “We still have yet to see a clinically significant cancer vaccine result. I think we will, but it hasn’t happened yet.” Several randomized controlled trials are now in the works that should clarify whether any of these strategies can consistently produce a measurable benefit, and to what extent. In the meantime, many questions remain.
It is uncertain when vaccines should be administered. Kandalaft and others believe that the best tactic is to act shortly after initial treatment—kicking the cancer when it’s down. “We should be vaccinating patients who are in remission and who are at high risk of relapse,” she maintains. In contrast, advanced disease gives tumors more of a home court advantage, allowing them to ensconce themselves in a more highly immunosuppressive environment. However, some of these tumors may still prove susceptible, and both Neon and BioNTech are now pursuing trials in metastatic disease. “We’ve observed that we have some advanced patients responding fast, after three months, with tumor shrinkage,” says Sahin.
The immunosuppression associated with advanced disease will likely necessitate combination with other immunotherapeutic agents to achieve a durable effect, although it seems likely that such pairings will also prove important in early disease settings. Indeed, many vaccine trials now in the works entail such combinatorial regimens.
Levy notes that amid the zeal to jam together different immunotherapies, researchers should be careful not to overlook other promising classes of cancer drugs with more indirect immunological effects. For example, his team has found that combinatorial treatment with a kinase inhibitor called ibrutinib, which is known to modulate the activity of a variety of immune cells, can enhance the potency of his group’s vaccination strategy. “It was very promising in the preclinical model,” says Levy. “We’ll see how it works in patients.”
Finally, it remains uncertain whether therapeutic vaccines might help crack immunologically “cold” tumors that have proven intransigent against other forms of immunotherapy. There are some signs that this could be the case, including a recent trial of a personalized vaccine that seems to elicit an immune response in patients with glioblastoma—one of the hardest targets out there.12
“If vaccines can really turn ‘cold’ tumors into ‘hot’ tumors, we will open the field for patients who really have no options,” predicts Kandalaft. “I would love to see that happen.”
Michael Eisenstein ([email protected]) is a freelance science writer and photographer.
References
1. link.springer.com/article/10.1007%2Fs40259-015-0140-7
2. www.nature.com/articles/nature22991
3. oncologypro.esmo.org/Meeting-Resources/ESMO-2018-Congress/A-Personal-Neoantigen-Vaccine-NEO-PV-01-with-anti-PD1-Induces-Broad-De-Novo-Anti-Tumor-Immunity-in-Patients-with-Metastatic-Melanoma-NSCLC-and-Bladder-Cancer
4. clinicaltrials.gov/ct2/show/NCT02897765
5. www.nature.com/articles/nature23003
6. clinicaltrials.gov/ct2/show/NCT03289962
7. stm.sciencemag.org/content/10/436/eaao5931.short
8. stm.sciencemag.org/content/8/368/368ra171.short
9. www.bidmc.org/about-bidmc/news/2018/05/cancer-center-at-bidmc-launches-immunotherapy-institute
10. stm.sciencemag.org/content/10/426/eaan4488.short
11. clinicaltrials.gov/ct2/show/NCT03410901
12. www.nature.com/articles/s41586-018-0810-y
