Cancer Vaccines: Activate the Immunosoldiers – Part I

The Experts
 

What successes have been seen so far with cancer vaccines?
 

Jens Bjørheim: The idea behind therapeutic cancer vaccines is that they will be administered post-diagnosis to direct the individual’s own immune system to fight cancer. Early on, researchers uncovered the remarkable potential of T cells to recognize and kill cancer cells, and that such T cells could be expanded using different vaccination technologies. Some of these vaccines generated a good immune response towards a tumor, but the clinical benefit for patients was disappointingly modest.  

Over the last decade, the development of therapeutic cancer vaccines has seen a new dawn, fuelled by the combination opportunities that followed the introduction of checkpoint inhibitors (CPIs). Comprehensive research has elucidated the restriction of T cells imposed by the immune checkpoints, representing a likely cause of the earlier failure of cancer vaccines. The CPI combination strategy is therefore likely to boost the T cell responses elicited by vaccination, which may in turn provide greater benefit to patients. Several clinical trials with combination therapies have demonstrated promising clinical efficacy in different cancer indications, and more interesting trials will read out soon. 

Myriam Mendila: With peptide-based vaccines, most phase III studies have not shown significant benefit for patients. In the past couple of years, however, we’ve seen encouraging data emerging for cancer vaccines based on mRNA technology. mRNA-based cancer vaccines have been tested in different clinical settings, and in early or metastatic disease settings in different cancer types, either as monotherapy or combined with PD-1 or PD-L1 antibodies. Data have shown interesting and long-lasting immunological responses in patients with advanced cancers. 

More recently, we have seen the first positive data from a randomized phase II trial evaluating an mRNA based cancer vaccine in patients with early-stage melanoma (Moderna’s 4157), where the mRNA vaccine in combination with an anti-PD-1 antibody reduced risk of recurrence in patients by more than 40 percent compared with treatment with the anti-PD-1 antibody alone. These early data, though often in small patient groups, raise hopes and expectations that we will be able to crack the challenges of cancer vaccines with mRNA technology in the not-so far future.

Nicolas Poirier: There are now at least three studies in three different indications with three different cancer vaccines that have reported promising results.

We’ve published positive results with a peptide-based cancer vaccine in monotherapy in a randomized phase III trial in metastatic and advanced lung cancer patients (B Besse et al., Annals of Oncology, 2023). Our data showed that in patients in acquired resistance to anti-PD(L)1, the cancer vaccine in monotherapy significantly improved overall-survival, reduced the risk of death by 41 percent in the first year, displayed three-fold less adverse events, and improved patients’ quality of life, as compared to chemotherapy. These positive results, for the first time in a randomized trial and in monotherapy, follow the positive phase II study that Moderna reported at the end of 2022 with a personalized cancer vaccine used in combination with anti-PD1 in adjuvant melanoma patients, where they reported a reduction of the risk of tumour recurrence and death by 45 percent. In mid-2023, BioNTech reported promising phase I results with a personalized cancer vaccine used in combination in adjuvant pancreatic cancer patients.

Justin Duckworth: Though there has been extraordinary success seen in the field of prophylactic vaccination, efforts to therapeutically vaccinate a patient when an infection or malignancy are established, often known as “post-exposure” vaccination, have yet to be successful. This was vividly demonstrated in the COVID-19 pandemic, where effective preventive vaccines were not effective in boosting natural immunity if an infection was already present. We must address this weakness by bringing vaccine-induced immunity closer towards the response our natural immune system mounts when it regularly deals with threats. 

Cancer vaccines represent perhaps the hardest challenge in the therapeutic vaccine field. Despite decades of effort, Dendreon’s Provenge in prostate cancer represents the only example of a therapeutic cancer vaccine that has received US marketing approval. What is striking about Provenge is that it is a hybrid of vaccination and cell therapy, attempting to target the vaccination directly to controlling cells of the immune network (dendritic cells). Whilst traditional vaccination relies on indirect recruitment of the cells governing one’s immune system, the concept of “cellular vaccination,” in which those cells are more directly engaged, has long intrigued immune therapists. Although successfully approved, Provenge still suffers from serious limitations around efficacy and cost because of how the therapy is manufactured.

The advent of mRNA vaccines has dramatically re-energized the field of anti-microbial and anti-cancer vaccinations. To enhance the potency of this approach, considerable efforts have been made to overcome the challenges of targeting malignant cells, and trials have been performed in combination with checkpoint inhibitors to alleviate the immune suppressive tumor microenvironment.

For those less familiar with this field, how exactly do vaccines prevent and/or treat cancer?
 

Paul-Peter Tak: Two antiviral preventative vaccines have been shown to decrease the risk of cancer. The first is the human papillomavirus (HPV) vaccine, which prevents acquisition of the virus that can lead to cancers of the oropharynx, cervix, and anogenital region. The second is the hepatitis B vaccine, which prevents acquisition of hepatitis B, whose infection is associated with development of liver hepatocellular carcinoma.

Most cancers, however, are driven by other causes, including genetic predispositions in the host, and/or exposure to carcinogens in the environment. The goal of therapeutic vaccination is to teach the patient’s immune system to recognize and eliminate tumor cells. Key challenges, however, are avoidance of clonal escape by tumor cells and the impact of the immunosuppressive tumor microenvironment. Induction of a broad immune response against multiple tumor-associated antigens and injection into the tumor while enhancing local inflammation may help to overcome the issues.

MM: Cancer is driven by alterations in the human genome. These genomic alterations accumulate over time and eventually lead to dysfunction of a cell in a way where a normal cell becomes a cancer cell that begins to replicate in an uncontrolled manner. Cancer cells should be recognized by the immune system as “foreign” in the same way the immune system recognizes pathogens, bacteria, and viruses, but often the immune system tolerates them. 

With therapeutic cancer vaccines, the aim is to overcome this immune tolerance. The concept is similar to what we do with infectious disease vaccines. For example, an mRNA cancer vaccine encodes for antigens that are specific to cancer cells in patients. Antigen-presenting immune cells, as well as other cells in the body, are transfected with the mRNA and instructed to present the cancer antigens encoded by the mRNA to other immune cells. With that, the immune cells are activated and taught how to identify cancer cells as malignant and destroy them.

JB: As a normal cell develops into cancer cells and eventually tumors, the cancer cells become increasingly different from their healthy counterparts, representing an opportunity for the immune system to detect and kill the cancer cells. The most well-described differences that are potential targets for the immune system are genetic mutations and the presence of proteins that are otherwise repressed. A cancer vaccine can be produced using molecules that mimic these changes observed in the tumor. There are many ways (platforms) that can be used to generate such molecules that the T cells can react to. Common platforms include peptides or DNA and RNA vaccines that encode for sequences of amino acids alike those of the abnormal tumor. Specific T cells then react to these molecules, and start to proliferate  searching for cancer cells that have the same mutated or  abnormal proteins.

NP: Essentially, cancer vaccines re-educate our immune system by providing the tumor antigens that the immune system should recognize but currently tolerates. Cancer vaccines can hence form new T-cell “troops” that can patrol and detect cancer cells expressing those tumor antigens. After surgery, when cancer vaccines are used as an adjuvant, the trained lymphocytes can detect remaining tumor cells and eliminate them to avoid tumor recurrence. In metastatic and advanced cancer patients, T lymphocytes have died or are highly exhausted, in particular after immunotherapy resistance. The cancer vaccine helps form new and fresh immune cells.

JD: Therapeutic vaccination of cancer is one of the most ambitious goals in medicine. It seeks to cure cancer in the same way our natural immunity protects us for much of our lives against nascent malignant cells, by tapping into the extraordinary specificity and firepower of the immune network. Everyone’s cancer is unique, making “one-size-fits-all” therapies challenging and crude by design. Cancer vaccines can be either generically targeted or personalized to a specific patient. The former can be expected to be less precise but with economic benefits. 

Which cancers can be targeted with vaccines – and why? 
 

NP: Our immune system is capable of eliminating tumor development as soon as it starts. When cancer sets in, it means tumor cells have avoided immune surveillance or hijacked immune regulatory mechanisms. In advanced cancers, some tumors are refractory to immunotherapy, which suggests that attacking the cancer with alternative immune-mediated mechanisms or technology is not the best option. However, most patients treated with immunotherapy will experience resistance after initial benefit. It means these types of tumors are immune-sensitive, but the immune response loses the first battle. If we could train new troops with a vaccine and send fresh immune cells to replace those that are dead or exhausted, then the immune response can once again lead the fight.

JB: In theory, vaccines can target all types of cancers. The fundamental principle is the immune system’s capacity to recognize and fight abnormal cellular changes. As long as the immune system can recognize mutated or abnormal proteins, vaccines can potentially be a viable treatment modality for any form of the disease.

MM: I agree; in principle, any type of cancer could be targeted with an mRNA-based cancer vaccine. Genomic alterations causing the cancer lead to the expression of tumor-specific proteins – also called tumor specific antigens – in the cancer cell. The trick is to identify these antigens so they can be encoded on mRNA and used in a vaccine. When the mRNA is translated into the tumor-specific protein it encodes for, it teaches and enables the immune system to differentiate tumor cells from healthy cells, so it can commence a targeted defence. 

Early data on therapeutic mRNA cancer vaccines have shown that it’s mainly the tumors that we qualify as “hot” tumors that respond best. These tumors are called hot tumors because their tissue is infiltrated by immune cells, indicating that the immune system is already active and present – and therefore more ready to respond to further stimulation.

However, we have also seen encouraging data in tumors that you wouldn’t necessarily call hot, such as pancreatic cancer. Here, the combination of an mRNA vaccine and PD-1 antibody has shown the potential to turn a cold tumor (little inflammation and presence of immune cells) hot. At present, the most promising approach in clinical trials is the use of mRNA in combination with another immuno therapy (usually a checkpoint inhibitor) in cancers that are sensitive to immunotherapies.

JD: There is much debate over which cancers represent the most promising targets for successful vaccination. Two lenses often used to view a tumor’s attractiveness for vaccination are mutational load and the tumor microenvironment. For mutational load, the greater the load, the more likely it is that the immune network can spot abnormalities on the surface of the tumor cell and target it for destruction. In the tumor locality, a loss of systemic and/or local T cell integrity increases the difficulty of creating a successful vaccine. T cell suppression in the tumor microenvironment and lymphoid organs is addressed by checkpoint inhibitors, though imprecisely because they target all T cells, regardless of their specificity, thus resulting in autoimmune side effects.

P-PT: Cancers that express consistent and unique tumor-specific antigens are natural targets for vaccination therapy, but they are not common. Many of the (neo)antigens are specific for the patient’s individual tumor, and would require sequencing and analysis of the tumor biopsies prior to treatment. Alternatively, biopsies could be used to support ex vivo expansion of cancer-specific immune cells that, once infused back into the patient, may recognize the tumor. However, these approaches are laborious and costly. 

An alternative approach is in situ vaccination, using viral immunotherapy, which, in principle, could work in any solid tumor. Here, an off-the-shelf therapeutic is injected into the tumor, with the aim of inducing tumor cell death, while promoting inflammation in the tumor microenvironment. Together, this creates optimal conditions to induce a broad immune response against the injected tumor and uninjected distant metastases. This can be achieved by viral immunotherapies that cause necrosis and inflammation in the tumor microenvironment, leading to a largely CD8+ T cell-mediated immune response.

An advantage of this approach is that it does not rely on a single antigen, which avoids clonal escape by tumor cells. Moreover, it does not require sequencing of the tumor or ex vivo stimulation of immune cells, which means it can be more easily implemented in clinical practice.

Check our Part II of the discussion here