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Simple Summary: The premise that certain checkpoint inhibitors are effective anti-cancer treatments beyond their immune modulatory capabilities influences current cancer research and clinical practice as well as future drug versus therapy development. We propose ways and means to enhance immunotherapy in cancer care by combining anti-PD1/L1 with various therapeutic modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications. [ABSTRACT FROM AUTHOR]

Simple Summary: According to the stem cell theory of cancer, we should be judicious with immunotherapy in cancer care. When we do not realize that cancer originates from a stem cell and has stem-ness capabilities, immunotherapy could be gratifying for the wrong reasons and challenging with a cautionary tale. A simple way to understand the immune system is to separate the self from non-self. If it is self, the immune system tolerates and spares. If it is non-self, the immune system attacks and destroys. Consequently, if cancer has a stem cell origin and is a stem cell disease, we have a serious problem and a major dilemma with immunotherapy. Because many refractory cancers are more self than non-self, immunotherapy may become an uphill battle and pyrrhic victory in cancer care. In this article, we elucidate cancer immunity. We demonstrate for whom, with what, as well as when and how to apply immunotherapy in cancer care. We illustrate that a stem cell theory of cancer affects our perspectives and narratives of cancer. Without a pertinent theory about cancer's origin and nature, we may unwittingly perform misdirected cancer research and prescribe misguided cancer treatments. In the ongoing saga of immunotherapy, we are at a critical juncture. Because of the allure and promises of immunotherapy, we will be treating more patients not immediately threatened by their cancer. They may have more to lose than to gain, if we have a misconception and if we are on a wrong mission with immunotherapy. According to the stem cell theory of cancer, we should be careful with immunotherapy. When we do not know or realize that cancer originates from a stem cell and has stem-ness capabilities, we may cause more harm than good in some patients and fail to separate the truth from the myth about immunotherapy in cancer care. [ABSTRACT FROM AUTHOR]

Simple Summary: We postulate that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We propose that the virus may turn out to be a surreptitious agent and a serendipitous model in our quest to investigate the origin of cancer. When it pertains, oncology recapitulates ontogeny, although genetic makeup is king. Cellular context may be the key to elucidating a stem cell origin of cancer. In 1911, Peyton Rous (Nobel Prize winner in 1966) demonstrated that a virus (i.e., RSV) caused cancer in chickens. In 1976, Bishop and Varmus (Nobel Prize winners in 1989) showed that the cellular origin of retroviral oncogenes was actually normal cellular genes (i.e., proto-oncogenes). In this article, we revisit the role viruses play in the genetic origin of cancer. We review a link between viruses or cancer and autoimmunity in an alternative stem cell origin of cancer. We propose that a virus is more likely to cause cancer when it infects a progenitor stem-like cell rather than a progeny differentiated cell. We postulate that both known (e.g., HBV and HPV) and novel viruses (e.g., SARS-CoV-2) pose an imminent threat in the emergence of chronic viral diseases as well as virally induced malignancies. Knowing the origin of cancer has profound implications on our current conception and perception of cancer. It affects our conduct in cancer research and our delivery of cancer care. It would be ironic if viruses turn out to be a useful tool and an ideal means in our quest to verify a genetic versus stem cell origin of cancer. When it pertains, oncology recapitulates ontogeny; although genetic makeup is pivotal, cellular context may be paramount to elucidating a stem cell origin of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Germ cell tumor of the testis (TGCT) teaches us that to cure cancer, we need to acquire and apply proper biological insight and clinical acumen. In 1946, about 90% of patients with metastatic TGCT died within the first year of diagnosis. Today, over 90% of the same patients are curable. This complete reversal in the cure rate of TGCT is not because we have designed better drugs (we have not), but because we have learned how to use the same drugs in the right patients under the right settings. Importantly, TGCT is a prototype stem cell tumor that may hold the key to unlocking the origin of cancers, thereby enhancing our understanding of cancer and improving the cure and care of patients with cancer. Germ cell tumor of the testis (TGCT) is a remarkably curable solid tumor even when it is widely metastatic and patently heterogeneous. It provides invaluable clues about the origin and nature of metastasis and heterogeneity, cancer dormancy and late recurrence, drug sensitivity and resistance, tumor immunity, and spontaneous remission that would enable us to enhance the cure and improve the care of patients with other currently intractable solid tumors. After all, germ cells are primeval stem cells and TGCT are a perfect stem cell tumor for us to investigate a stem cell versus genetic origin of cancer. In many respects, TGCT is a prototype stem cell tumor that will enable us to elucidate the role of differentiation versus dedifferentiation in the evolution of a complex mixed tumor. It will help us decipher relevance of the genome versus the epi-genome in a progenitor cancer stem cell versus a progeny differentiated cancer cell. Importantly, clarification of a cellular context versus the genetic makeup in cancer has immense clinical implications. We postulate a unified theory of cancer derived from seminal TGCT research to improve personalized cancer care. Contrary to current norms and conventional wisdom, we propose that when it concerns a complex rather than simple cancer and a mixed rather than pure tumor (which is practically all solid tumors) multimodal therapy trumps targeted therapy and integrated medicine overrides precision medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Although testicular germ cell tumor (TGCT) carries a high cure rate, some patients still die from it. We investigated the genetic landscape and cellular origins of cancers that develop later in life after treatment for TGCT and found evidence that a common progenitor cell might be responsible for both. This study shows the possible importance of stem-like cells in the development of cancer. Although genetic changes may be pivotal in the origin of cancer, cellular context is paramount. This is particularly relevant in a progenitor germ cell tumor and its differentiated mature teratoma counterpart when it concerns tumor heterogeneity and cancer dormancy in subsequent second malignancies (subsequent malignant neoplasms (SMNs)). From our tumor registry database, we identified 655 testicular germ cell tumor (TGCT) patients who developed SMNs between January 1990 and September 2018. Of the 113 solid organ SMNs, 42 had sufficient tumor tissue available for fluorescence in situ hybridization (FISH) analysis of isochromosome 12p [i(12p)]. We identified seven additional patients for targeted DNA and RNA sequencing of teratomas and adjacent somatic transformation. Finally, we established cell lines from freshly resected post-chemotherapy teratomas and evaluated the cells for stemness expression by flow cytometry and by the formation of teratomas in a xenograft model. In our cohort, SMNs comprising non-germ cell tumors occurred about 18 years after a diagnosis of TGCT. Of the 42 SMNs examined, 5 (12%) contained i(12p) and 16 (38%) had 12p gain. When comparing a teratoma and adjacent somatic transformation, targeted DNA and RNA sequencing demonstrated high concordance. Studies of post-chemotherapy teratoma-derived cell lines revealed cancer-initiating cells expressing multipotency as well as early differentiation markers. For the first time, we demonstrated the prevalence of i(12p) in SMNs and the presence of progenitor cells embedded within mature teratomas after chemotherapy. Our findings suggest a progenitor stem-like cell of origin in SMN and TGCT and highlight the importance of cellular context in this disease. [ABSTRACT FROM AUTHOR]