By Kim Margolin, M.D., FACP, FASCO

Recap and background on tumor vaccines

We last visited the topic of vaccines in September of 2021, and in the three years since then, remarkable progress has been made in the field of cancer immunotherapy, including the development and testing of vaccines that now have great promise in the treatment of cancer. Most cancer prevention vaccines, meanwhile, remain “not ready for prime time.”

At the time of the last review, much of the article was about general principles of vaccine biology, technical aspects of vaccine preparation, and medical applications of a small number of strategies that could be considered tumor vaccines but are highly complex. For example, an immune cell-based vaccine against prostate cancer, sipuleucel-T (Provenge), is produced by exposing patient dendritic cells (a type of white blood cell) to a protein made from attaching a tumor-nonspecific antigen, prostatic acid phosphatase (PAP), to a growth- and immune-enhancing protein, granulocyte-monocyte colony stimulating factor (GM-CSF). When a bag of these cells is infused back into the patient’s vein, a modest immune response against prostate cancer can be detected among the T-lymphocytes—the immune cells that seek to detect and destroy cancer cells. These patients live longer and experience a delay in symptoms related to advanced prostate cancer than those who do not receive this treatment.¹

Many other attempts (with little success) have been made to use this form of tumor vaccine against cancer—taking advantage of the fact that dendritic cells are considered mother nature’s most potent antigen-presenting cells (cells that are required for the body to take up and process foreign invaders like infectious organisms and malignant cells) and are key players in the activation of T cells to perform immune-based killing. Our tissues are simply too efficient at controlling overactive immune responses after they’ve protected us—and thus, we often don’t control necessary immune responses against cancer. Tumor cells have also evolved—exactly as described by Darwin—to escape immune-mediated killing by producing factors that are immunosuppressive, causing the T cell response to be ineffective in multiple ways.

Another complex approach to tumor vaccine that has enjoyed greater application and is pertinent to melanoma (detailed in both the intratumoral therapies and vaccines episodes of In Plain English) is the herpes simplex virus-based TVEC (Imlygic). This vaccine consists of a genetically engineered form of herpes simplex (the virus that causes cold sores) as well as the gene for GM-CSF, the same immune-stimulating drug mentioned above. (It does not cause a herpes infection.) When injected directly into tumor metastases, TVEC delivers its DNA to tumor cells, which take up the genes and produce GM-CSF in the region of the tumor, thus immunizing the patient against tumor antigens by drawing immune cells into the area. While the success of this approach is limited to relatively small, easily-injectable tumors, it is capable of causing regression even at distant, uninjected metastases. Newer vaccines intended for similar direct injection with different engineered genes are being tested both alone and in combination with some of our other highly-active immunotherapy drugs such as nivolumab (Opdivo) or pembrolizumab (Keytruda) and appear very promising in melanoma. These types of vaccines are called “oncolytic virotherapy” for their ability to cause direct destruction of the injected tumor as a way of introducing tumor antigens to immune cells.²

Introduction to the role of mutated DNA as a basis for tumor vaccine

Possibly the most exciting strategy in the field of tumor vaccine development for advanced cancer has emerged over the last three years and arose out of remarkable success and speed in the development of vaccines against the Covid-19 virus starting in 2020. The company that first announced success in this area—a German company called BioNtech, under the wife-husband research team of the Turkish scientists Ozlem Tureci and Ugur Sahin— had originally been working on a vaccine against cancer but turned those efforts and applied the technology to Covid-19 to address the ravages of the worldwide viral pandemic.

Mutated DNA, which occurs in all cancers, ultimately provides the patterns for our cells to make mutated proteins, which can be recognized by immune cells as foreign and are thus targeted for killing by the immune cells.

From these studies emerged the concept of a tumor mutation burden (TMB), which is a measure of how many abnormal sequences, or mutations, are detected in a specific amount of tumor DNA when compared with the normal tissue of the relevant organ. And from that concept came a remarkable finding: Generally (but not in all tumor types), the higher the tumor mutation burden, the more likely the cancer will respond to immunotherapy. A threshold of about 10 or more mutations among every 1000 of the basic units in DNA has been used to distinguish high from low tumor mutation burden. Melanoma, which almost always features a significant amount of sun-induced DNA damage, usually has a TMB well over 10, except when it arises, in rare cases, from the internal membranes (mucosal melanoma) or the pigmented tissues of the eye (uveal melanoma), which have little to no sun exposure and very few mutations.

In the case of tumors with very low TMB, a potent antitumor immune response may still occur—instead of a large number of mutations adding up to make an adequate immune response, a single strong antigenic stimulus can occur in a few cancers that are known to be caused by viruses. For example, head and neck cancer and cervical cancer are often caused by a virus called HPV, and the rare skin cancer Merkel cell carcinoma is frequently due to a related virus, the Merkel cell polyoma virus. Virus antigens are more potently recognized by our immune system, in part because they are more threatening to our health, and in part because the immune system has not been exposed to those antigens over a long period and become tolerant to their presence.

How is a tumor neo-antigen vaccine produced and tested?

The field of sequencing and analyzing the mutations in tumor genetic material has grown tremendously with the advent of high-throughput machines and informatics, including machine learning and artificial intelligence applications. These developments have allowed researchers to discover and select the most immunogenic protein fragments used in neo-antigen vaccines and to produce vaccines from the messenger RNA (mRNA is the genetic material based on DNA sequences that provides the pattern for the sequence of all of our body’s proteins). It is relatively easy to produce specific mRNA sequences in the laboratory and to tag these mRNAs with various substances that provide functions such as the uptake of these mRNAs into tumor cells, detailed below.

Immunologic intelligence is critical here, as there are many checks and balances in the immune response; thus, not only is it important to select the best sequences but it is also necessary to know which ones might compete or even cause immune suppression or exhaustion of immune cells due to overly strong responses to antigens delivered repetitively into the patient. The strategy taken by the current developers of tumor neo-antigen-based vaccines is to select the best antigenic sequences predictive of an immune response (these predictions are done with AI, and the current protocol is based on the selection of 34 such sequences). The synthetic mRNA is then wrapped in a lipid nanoparticle (a tiny ball of mRNA wrapped up inside of a layer of a fatty substance that facilitates its uptake into antigen-presenting cells as detailed earlier in this issue). There, the mRNA performs its usual function of encoding protein or protein fragments that are then utilized by immune cells to elaborate an immune response and immunize the patient against tumor antigens.

To date, the mRNA/lipid nanoparticle approach has been limited to investigation in the adjuvant setting, where tumor has been removed surgically but based on its stage has a high risk of relapse. Relapses come from the growth of tiny particles of tumor, sometimes only one or a few cells, that escaped from the primary tumor prior to its surgical removal. This is the stage at which most animal experiments have shown the greatest likelihood that a tumor vaccine will work to reduce the chance of relapse and, hopefully, prolong survival. Further, it is likely that the combination of vaccine with our other most powerful immunotherapy, the immune checkpoint blocking antibodies (such as nivolumab or pembrolizumab) will provide a higher likelihood of benefit.

This possibility has already been tested in a randomized study of patients with resected melanoma at high risk of relapse, in which 2/3 or approximately 100 patients received the standard adjuvant immunotherapy (pembrolizumab for one year following surgery) and the remaining patients (just under 50) also received a vaccine based on their own tumor’s neo-antigens, based on the mutations found in the DNA sequences of tissue removed at the time of surgery. Early analysis of this study, which enrolled about 135 patients, has shown a large benefit for the combination, and a confirmatory study is expected to provide sufficient data in a larger number of patients to support approval by the FDA of this vaccine combination for patients with resected melanoma at high risk of relapse.³

In memoriam

It is largely through the efforts of Dr. Jeffrey Weber and his colleagues that this study and many prior research projects focused on developing melanoma vaccines were possible. We would like to acknowledge the lifelong efforts of Dr. Weber, who devoted his research career to cancer immunotherapy and the development of effective vaccines against melanoma and other cancers. Dr. Weber recently succumbed to pancreatic cancer, a disease for which immunotherapy has failed to move the needle but for which enormous efforts continue, to achieve effective treatment for this devastating malignancy. We thank Dr. Weber and recognize his life’s work on behalf of patients with melanoma and others in the development of highly effective cancer immunotherapy.

Questions on this article may be submitted to Alicia@AIMatMelanoma.org

Dr. Margolin is a Medical Director of the SJCI Melanoma Program, St. John’s Cancer Institute. She worked at City of Hope for 30 years and also held faculty positions at the Seattle Cancer Care Alliance/University of Washington and at Stanford University. Among her academic achievements were long-term leadership of the Cytokine Working Group, leadership involvement in the Cancer Immunotherapy Trials Network, participation in the Southwest Oncology Group’s Melanoma Committee, and many positions in the American Society of Clinical Oncology and the Society for Immunotherapy of Cancer. Dr. Margolin has reviewed grants for many cancer-related nonprofit organizations and governmental agencies. She has also served as a member of the Oncology Drugs Advisory Committee to the FDA, the American Board of Internal Medicine’s Medical Oncology certification committee, and the Scientific Advisory Committee of the European Organization for the Research and Treatment of Cancer.

Dr. Margolin collaborates with AIM at Melanoma to write our In Plain English articles to provide timely updates on new developments for patients, caregivers, and other individuals with an interest in medical advances in melanoma.

References

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