new visions in cancer research

Q: What are your thoughts on the relationship between cancer immunogenicity and amenability to cancer vaccinations across the three prevention modalities?

A: Cancer research over the past 20 years has clearly shown that cancer is a highly heterogeneous disease. This heterogeneity exists not only across different organs affected but also within the same cancer type in different patients. The "Anna Karenina principle" applies here: "All happy families are alike; each unhappy family is unhappy in its own way."

Healthy cells share common attributes, while cancer can arise from a variety of different cellular dysfunctions. For cancer prevention, this means carefully mapping this diversity and identifying common patterns to design broadly applicable prevention strategies. This is a significant challenge, but the fact that even low-immunogenic or "cold" tumors (those without infiltrating immune cells) can respond to immunotherapies offers hope. Prevention strategies, if carefully designed, could be effective even in these cases.

Q: The challenge of identifying the best oncoprotein for targeted therapies (e.g., vemurafenib against BRAF V600) seems similar to identifying the best oncoantigen(s) for vaccine development. Is there a fundamental difference?

A: While the general goal is the same, the development, methods, and formulations differ significantly. Both targeted therapy and oncoantigen vaccines focus on targets essential for cancer etiology. However, targeted therapies aim to block these pathways to counteract cancer growth, while cancer vaccines aim to elicit immune responses against these targets because their essentiality implies their presence, especially at early stages. The mechanisms of action are substantially different (small molecules, monoclonal antibodies vs. antigen administration), and target identity may also differ (not all oncoproteins are immunogenic). The shared challenge is identifying targets strictly essential for cancer development or progression. If a target isn't sufficiently crucial, cancer cells can downregulate its expression or compensate with other mechanisms, leading to therapy resistance in both cases.

Q: What biomarkers, other than genetic predisposition, would establish a favorable benefit/risk ratio for cancer vaccination in primary prevention?

A: For immune efficacy, one can look at antigen immunogenicity. Not all predicted antigens are empirically immunogenic. But your question is broader. We don't know yet. Carefully designed longitudinal studies are needed to assess vaccine benefit and prevention potential. Only through population stratification and tested indicators can we identify powerful biomarkers to guide administration to healthy populations. Current "suspects" include genetic predisposition, lifestyle habits (nutrition, smoking), and exposure (e.g., asbestos).

Q: Is it possible to develop a vaccine against a wild-type proto-oncogene that is simply overexpressed? In other words, is there a dose-response phenomenon in the presentation of self-antigens (MHC1 and/or MHC2), with a threshold above which immunity "kicks in" and safely eliminates cells that overexpress a proto-oncoprotein?

A: I believe so. As we mention in our article, tumor-associated antigens (antigens also present on healthy somatic cells) have been successfully and safely targeted in hundreds of therapeutic clinical studies. The primary challenge has been eliciting a sufficient immune response to clear the tumor, rather than an excessive response posing a health threat. I believe the same principle applies to proto-oncogenes. We need to carefully identify targets essential for cancer onset or progression and then design appropriate treatment regimens (dose, formulation, etc.) to ensure safety without compromising efficacy.

Q: Glycosylation is often altered in cancer cells. What are your thoughts on focusing on this aspect to identify useful antigens (e.g., a vaccine against a particular glycoform or set of glycoforms)?

A: It may be a future direction, but we're not ready yet. Identifying and manufacturing peptides targeting cancer antigens is relatively easy now, and proteins/antigens are quite stable. A major risk is antigen loss (downregulation by cancer cells). Sugars are different. Glycosylation creates novel epitopes, sometimes cancer-specific, that could be targeted. However, these modifications are more dynamic (reversible) and less specific (limited sugar moieties, also found in healthy conditions). These are more difficult targets, at least currently.

Q: A fundamental challenge in immunotherapy is converting "cold" tumors to "hot" tumors. How relevant is this to cancer vaccine development?

A: This is critical, perhaps the most critical factor along with antigen identification. A key advantage of cancer prevention strategies (especially secondary prevention, in pre-cancerous lesions or early-stage cancer) is the often less immunosuppressive tumor microenvironment (TME) compared to advanced tumors. This makes targeting a more immunocompetent environment highly favorable for earlier cancer vaccines, either in early-stage disease or even in healthy individuals (especially those with risk factors like smoking or genetic predisposition). This increases the chance of a robust and effective immune response.

Q: Can "tumor-heating" signaling molecules (e.g., pro-inflammatory cytokines) be considered vaccine adjuvants?

A: Absolutely. Vaccine adjuvants, while simply defined as agents that increase or modulate the immune response, have complex classifications and mechanisms of action. We often use them empirically without fully understanding how they work. Systematic comparisons of adjuvants and dissection of their combinatorial or synergistic actions are needed. So, yes, they can be considered as such, but we've only scratched the surface.

Q: What are your thoughts on identifying antigens specifically present in cancer stem cells, a type of vaccine against metastasis (tumor-initiating cells)? There seems to be progress in more robust, functional definitions of cancer stem cells and methods for isolating them.

A: Cancer stem cells are attractive targets due to their association with tumorigenesis and metastasis. However, our review advocates a paradigm shift in how we view cancer vaccines. Our long-term goal is robust, effective vaccines acting at early disease onset or even before cancer occurs (true primary prevention). This would eliminate the need to target cancer stem cells, as they wouldn't have a chance to arise. It may seem utopian, but we won't know unless we try.

Q: What are your thoughts on the importance of the delivery route for cancer vaccines, particularly mucosal vaccines, which present antigens to a rich repertoire of sentinel cells, antigen-processing cells, and effector cells, as opposed to injectable vaccines?

A: You are absolutely right, and there is indeed a great deal of studies currently exploring this route and that we do not have the chance (or the space) to review in our manuscript. What I can briefly say here is that also the administration route plays a crucial role when designing prevention campaigns. If the vaccine is easy to administer it may not require health professionals, making it cheaper and more easily accessible; moreover, an easier administration can also be more easily accepted by the population. In addition to these practical, but not lesser, aspects, as you said, the mucosal is a highly immunocompetent tissue that can be definitively exploited also for cancer vaccines. A future mucosal vaccine will have to ensure both the safe and efficient administration of antigens through a tissue that is specifically designed as a barrier against external agents. While this is not trivial, there are several promising formulation and biomaterials currently in investigation for cancer vaccine administration; the future will tell us if it was a good horse to bet on, but I believe so.  

Q: A challenge in developing targeted therapies is finding sufficiently abundant oncoprotein alleles (e.g., BRAF V600) for a "one drug-one target" paradigm. Vaccine design seems different; a pooled peptide vaccine could include epitopes from several oncoproteins, conceptually like combination therapy. Your thoughts?

A: To answer your question, I think it is purely a matter of cost, time and effort. Your question brings to my mind a crucial scene in the notorious film “Contact” by Robert Zemeckis. When the scientist played by Jodie Foster discovers that the machine built to contact extraterrestrial life was destroyed by a religious fanatic, a government representative tells her not to worry because the government has secretly built a second one. His explanation was simple: “why build only one machine when you can build two, at double the cost?”. 

We are in the same situation here (except for secrecy). Multiple targeting is beneficial, lowering the risk of selecting therapy-resistant cancer cells that thrive by losing single targets. However, this requires additional resources for identifying, testing, validating, and producing a multi-target vaccine. Multiplying targets also increases the chance of off-target effects and hypersensitivity. These considerations must be balanced in early studies to determine the minimum or ideal number of targets. Much work remains.

Q: How do you see AI advancing cancer vaccinology?

A: AI is increasingly shaping our lives and positively influencing scientific research. Large dataset analysis and identification of novel antigens (multi-omics approaches) are areas where AI and high computational power can accelerate progress. AI can also support cancer detection and promote earlier intervention, helping identify patients who could benefit from cancer vaccines (e.g., secondary prevention).

Q: How do you see CRISPR (and other gene-editing technologies) advancing cancer vaccinology?

A: CRISPR is another powerful tool. It could be used in targeted therapy to silence or reactivate signaling pathways aberrantly deregulated in cancer, restoring physiological conditions. For cancer vaccines, it could be used for antigen delivery, instructing antigen-presenting cells to express chosen antigens. However, CRISPR still has drawbacks (off-target effects, efficiency limits, packaging challenges, genome integration risks). We have more efficient, cheaper, and easier methods (like mRNA) for antigen delivery, and I think we should currently focus on these.

Q: Cancer genomics has generated an astronomical dataset on cancer-associated mutations, perhaps over-simplistically classified as "drivers" or "passengers." For vaccination purposes, isn't it true that: i) this classification is of limited use? and ii) what matters is specific, strong antigenicity for an effective and safe immune response, and sufficient prevalence in the target population?

If so, are there efforts to identify such mutations? I'd guess "omics" and AI could help predict actionable epitopes resulting from these mutations.

What are your thoughts?

A: Driver and passenger mutations differ significantly. Passenger mutations are more abundant, especially in tumors with a high mutational load. While easier to identify (we don't need to validate their active role in carcinogenesis), and thus frequently used in neoantigen vaccination campaigns, they are usually patient-specific and not applicable to multiple patients. Driver mutations are more appealing because, linked to disease occurrence or progression, they are likely shared across patients, enabling larger-scale targeting. Also, their functional role makes them less likely to be silenced or lost, preventing cancer escape. "Omics," AI, and increased computational power are incredible tools for identifying effective antigens. For example, huge efforts are underway to map pre-malignant conditions to identify immunodominant epitopes and disease-controlling antigens for preventive approaches. These tools, as you mentioned, will drive and shape the future of cancer vaccines.

Q: Do you see cancer vaccine R&D as a subfield of immunotherapy, or should it become a distinct discipline due to its unique "thinking"?

A: That's a tricky question. Historically, cancer vaccines evolved within cancer immunotherapy. While cancer conferences often have vaccine sessions, immunology conferences less so. However, for success, we need collaboration. Only by working synergistically with experts from various fields can we address scientific questions from all angles. We shouldn't operate as a separate entity but maintain close connections with doctors, immunologists, engineers, biologists, and others. Whether vaccinology professors belong to a biology or immunology department is less important than this interdisciplinary collaboration.

Q: One lesson from the COVID-19 pandemic is that scientists and public health officials need to communicate better with the public. Beyond specific campaigns (e.g., HPV vaccination), how can we gain (or regain) public trust in cancer vaccine research and outcomes?

A: This is a major challenge. Focusing on results is crucial. Smallpox eradication, a monumental achievement comparable to the moon landing, was vaccine-driven. Similarly, HPV vaccination campaigns have drastically reduced liver cancer cases (where HPV is a recognized risk factor). These successes are undeniable and demonstrate the power of vaccines. Outreach campaigns and school initiatives targeting young people can greatly raise awareness and build trust in science. Scientists should be active social players, engaging with the public to demonstrate their role and importance, rather than remaining isolated in labs.