now that we are aware of the genetic diversity of cancer with both intratumor and intertumor antigen heterogeneity , the past process of antigen discovery becomes a prime suspect for the failures of cancer vaccines . it is not enough to have a presumptive antigen but more relevant to have and use functional , tumor - specific antigens . it is understandable why none of the allogeneic tumor cell vaccines have provided significant clinical benefit . there is a paucity of functional tumor antigens that are universally expressed , strongly immunogenic , and cancer - specific , unless the antigen discovery involves autologous tumor cells . it is improbable to select any one of the 50 or so common marker proteins that may be expressed in some but not all tumors , or the rare possibly shared antigens . when evaluating all of the antigen discovery activity thus far , it is clear that there has been a paucity of shared tumor - associated antigens that would provide a homogeneous immunity to antigenically heterogeneous tumors . a further complication is that even if a cocktail of antigens were identified that could provide broad coverage , multiple companies might control the intellectual property associated with these antigens , and suitable business agreements can be hard to achieve , especially if more than two companies are involved . in addition , the development of a robust cytotoxic , cell - mediated immune response with any single protein that can successfully destroy antigenically polyvalent tumor cells is unlikely to achieve major clinical benefit . therefore , it is essential , with all that we have learned at both the tumor genomic and immunotherapeutic level , to reevaluate the antigen discovery process and the consideration of a universal or even comprehensive immunological target(s ) . the use of the patient s own tumor to a robust tumor - specific immune response is the purest approach to deal with tumor cell antigen heterogeneity . the fda recognizes autologous tumor cell vaccines in the guidance for industry : clinical considerations for therapeutic cancer vaccines ( in review , 2012 ) . their guidance in this area was likely not prompted by the recent tumor cell genomic diversity data . their guidance is more likely based on the use of dendritic cells which involves a process of expansion in cell culture , rather than using the patients own tumor cells . they point out the following :  design of studies using autologous vaccine products that are derived from the patients own tumors poses unique challenges and deserves some special considerations . manufacturing such vaccines can take a considerable period of time and in some instances , may take up to several months . if complete remission or stable disease is eligibility criteria , the time required for manufacture may mean that , some trial subjects may not remain eligible because of disease recurrence or progression . however in our experience , the time required for dissociation of parenchymal stage ii and iii colon tumor cells , into a sterile live - cell drug product is ~6 h. the quality control takes 21 d , primarily to include the sterility test . consideration should be given to optimization of the vaccine manufacturing process prior to late phase clinical trials in an effort to increase the proportion of the patients who are randomized to the treatment arm and receive the active product . autologous tumor cells is a new paradigm in vaccine manufacturing and has more logistical and regulatory aspects than have been engaged in past processes . however , one has to choose the route that complies with the available tumor biology and immunotherapeutic data . in our case in the beginning the logistics was a glass half empty . it was earlier noted that the only fda approved cancer vaccine product is an autologous vaccine using expanded dendritic cells carrying a tumor - associated peptide pa2024 , the recombinant fusion protein of human pap with gm - csf , prior to reinfusion to the metastatic castration - resistant prostate cancer patient . the drug  provenge ( sipuleucel - t ) provides patients approximately nine weeks in median overall survival improvement . the $ 93,000 per treatment cost makes for an unfavorable pharmacoeconomic analysis , $ 270,000 dollars per life - year gained . as new autologous vaccine processes develop , the logistics will be improved and the cost / benefit ratio should also improve as seen with many new and developing drug products . another source of antigenically responsible autologous tumor cells can be the circulating tumor cells ( ctc ) , a distinct population of cancer cells found in circulation in blood . also , there is speculation that within the ctcs there are cancer stem cells ( csc ) , which have the ability to give rise to metastatic tumors . more and more data suggest that csc play a significant role in tumor evasion of the several standard cancer treatment modalities . from an active specific immunotherapeutic point of view , the cancer stem cells should possess not only the variety of intertumor diversity but also the tumor - specific antigens , which would induce a broad tumor - specific immune response in the host . we could question why this does not happen naturally , the plausible reasons can be dosage , route of exposure to the immune system , requirement for a strong immunostimulant for homing of effector cells . to provide more accurate evidence for the csc within ctcs , several approaches will need to be mounted ; these would be techniques based on cell culture , flow cytometry , and molecular - based techniques . the latter is based on the fact that the csc phenotype is defined by multiple markers which would also include gene expression analysis . these studies are being applied to various solid tumors such as breast cancer , pancreatic cancer , lung , melanoma , sarcoma and other tumors ( tang ) . finally , there are other considerations that need to be studied and correlated with the knowledge of heterogeneity in order to develop effective and beneficial cancer vaccines . these would involve understanding and extending the relationship of the mhc class 1 regulatory factors associated with cell - membrane - localized tumor antigens . the use of the patient s own tumor to a robust tumor - specific immune response is the purest approach to deal with tumor cell antigen heterogeneity . the fda recognizes autologous tumor cell vaccines in the guidance for industry : clinical considerations for therapeutic cancer vaccines ( in review , 2012 ) . their guidance in this area was likely not prompted by the recent tumor cell genomic diversity data . their guidance is more likely based on the use of dendritic cells which involves a process of expansion in cell culture , rather than using the patients own tumor cells . they point out the following :  design of studies using autologous vaccine products that are derived from the patients own tumors poses unique challenges and deserves some special considerations . manufacturing such vaccines can take a considerable period of time and in some instances , may take up to several months . if complete remission or stable disease is eligibility criteria , the time required for manufacture may mean that , some trial subjects may not remain eligible because of disease recurrence or progression . however in our experience , the time required for dissociation of parenchymal stage ii and iii colon tumor cells , into a sterile live - cell drug product is ~6 h. the quality control takes 21 d , primarily to include the sterility test . consideration should be given to optimization of the vaccine manufacturing process prior to late phase clinical trials in an effort to increase the proportion of the patients who are randomized to the treatment arm and receive the active product . autologous tumor cells is a new paradigm in vaccine manufacturing and has more logistical and regulatory aspects than have been engaged in past processes . however , one has to choose the route that complies with the available tumor biology and immunotherapeutic data . in our case in the beginning the logistics was a glass half empty . it was earlier noted that the only fda approved cancer vaccine product is an autologous vaccine using expanded dendritic cells carrying a tumor - associated peptide pa2024 , the recombinant fusion protein of human pap with gm - csf , prior to reinfusion to the metastatic castration - resistant prostate cancer patient . the drug  provenge ( sipuleucel - t ) provides patients approximately nine weeks in median overall survival improvement . the $ 93,000 per treatment cost makes for an unfavorable pharmacoeconomic analysis , $ 270,000 dollars per life - year gained . as new autologous vaccine processes develop , the logistics will be improved and the cost / benefit ratio should also improve as seen with many new and developing drug products . another source of antigenically responsible autologous tumor cells can be the circulating tumor cells ( ctc ) , a distinct population of cancer cells found in circulation in blood . the ctcs can be considered as progenitors of relapse . also , there is speculation that within the ctcs there are cancer stem cells ( csc ) , which have the ability to give rise to metastatic tumors . more and more data suggest that csc play a significant role in tumor evasion of the several standard cancer treatment modalities . from an active specific immunotherapeutic point of view , the cancer stem cells should possess not only the variety of intertumor diversity but also the tumor - specific antigens , which would induce a broad tumor - specific immune response in the host . we could question why this does not happen naturally , the plausible reasons can be dosage , route of exposure to the immune system , requirement for a strong immunostimulant for homing of effector cells . to provide more accurate evidence for the csc within ctcs , several approaches will need to be mounted ; these would be techniques based on cell culture , flow cytometry , and molecular - based techniques . the latter is based on the fact that the csc phenotype is defined by multiple markers which would also include gene expression analysis . these studies are being applied to various solid tumors such as breast cancer , pancreatic cancer , lung , melanoma , sarcoma and other tumors ( tang ) . finally , there are other considerations that need to be studied and correlated with the knowledge of heterogeneity in order to develop effective and beneficial cancer vaccines . these would involve understanding and extending the relationship of the mhc class 1 regulatory factors associated with cell - membrane - localized tumor antigens . a superficial analysis of the cancer vaccine immunotherapy field , considering the enormous number of failures and the relatively minimal benefits of the one registered autologous product may seem to cast doubt on the future of this clinical approach to treating solid tumors . however , there is a light at the end of the tunnel . new sophisticated genomic studies have better characterized the molecular and genomic biology of tumor cells beyond the homogenous profile proffered by routine pathologic and histochemical classifications . understanding the genetic basis of antigenic heterogeneity is a very important realization to immunologists . clearly patient - specific therapies such as immunotherapy need to be conducted with the relevant , functional antigens / targets . it is now recognized that the more relevant clinical setting for cancer vaccines is in adjuvant setting in occult - disease patients . there is a great deal of potential yet to be realized using relevant cancer vaccines alone and in combination therapies with non - immunosuppressive cytotoxic drug therapies . it is a matter of fact that the greatest advances in the development of successful clinical treatments have been achieved based on a more precise understanding of the functional biologic basis of the particular disease . we have realized for over 30 y that cancer is a genetic disease and that malignancy , or unregulated growth , is a consequence of mutations . in fact the impetus for the search for  oncogenes  was a natural consequence of this knowledge , and the failure to find such a universal cancer - specific gene(s ) should have been an indication that there was greater diversity or heterogeneity than originally expected . the explosion of the dna sequencing technology and implementation has certainly validated the current perception of tumor cell biology , as possessing both intertumor and intratumor heterogeneity . from an immunologic viewpoint , this makes the previous concepts of antigen discovery for cancer vaccines impractical and problematic , with the implication that one of the soundest approaches would employ autologous tumor cells . this new paradigm for patient - specific immunotherapy will be more complex , and while there will be greater benefit and safety , this approach may require a retrofitting that is at odds with current clinical oncology and pharmaceutical standards and methodologies . this , however , is the beginning of greater progress in the area of patient - specific , active immunotherapy .
for nearly two decades there has been an abundance of research and clinical development programs underway to develop active specific immunotherapies , to educate the patient s immune response , specifically the t - cell immunity and memory , to recognize and destroy tumor cells by cell - mediated cellular toxicity . while many of these technology platforms achieved promising results in preclinical and clinical phase i and ii clinical trials , essentially all but one have failed to achieve fda market approval as a therapeutic drug product .