Background:

With over 19.3 million estimated new cases and almost 10.0 million deaths in 2020, cancer has again been shown to be among the leading causes of both morbidity and mortality worldwide. 1 For years this tremendous burden has been the impetus for research and further advancement of therapies in the treatment of cancer, although limitations remain, especially in metastatic disease which is often resistant to treatment. 2 In recent decades the advancement of immunotherapies has begun to offer a potentially powerful new weapon in the armory of therapies against cancer, specifically through their ability to modify immune functioning to target cancer.3 When compared to contemporary therapies, immunotherapy offers several advantages.  These include (1) the ability to target cancer cells which may not be rapidly dividing, (2) the ability of the immune system to reach areas of the body that were previously inoperable, and (3) the ability to potentially target microscopic disease and disseminated metastasis.3 α-Gal Hyperacute technology has been described as one such promising immunotherapy.

Application of alpha-Gal Hyperacute Technology in Cancer

Historically it has been known that poor uptake of tumor antigen by antigen-presenting cells (APC) through tolerance mechanisms has been a limitation on the immunogenicity of previously developed cancer vaccines. 4 This barrier to uptake can be combated through the exploitation of alpha-Gal hyperacute technology.  Hyperacute technology is able to exploit the naturally circulating anti-Gal-IgG antibody to facilitate the opsonization and uptake of any molecules complexed to alpha-Gal. IgG antibodies are particularly useful in opsonization since APC all express Fcgamma receptors which readily interact facilitating effective uptake, internalization, and maturation of the APC. This leads to the cross-presentation of the  by on class I and class II MHC molecules of the APC. 4 

If the alpha-Gal molecule was complexed to a tumor associated antigen (TAA) either directly or by sharing a membrane with the antigens, the opsonization by pre-existing IgG can lead to APC activation and maturation. This leads to the cross-presentation of TAA by on class I and class II MHC molecules of the APC. 4 The ability for the anti-Gal-IgG to encourage opsonization and antigen presentation of the TAA enables a means by which T cells can overcome tolerance mechanisms and become activated targeting the tumor antigens directly.

The role of hyperacute technology as a potential cancer immunotherapy showed promise in early research.  Animal models demonstrated that this technology not only was efficacious in reducing tumorigenicity but also was able to directly target disseminated metastasis.  Moreover, the early research also suggested that hyperacute technology may be able to be utilized as an off the shelf solution for cancer. (8) These early investigations were met with optimism that hyperacute technology may be a novel and powerful approach to cancer immunotherapy.

The Early Prospects of Animal Models

The early optimism which surrounded hyperacute technology was largely based on mouse models and their effectiveness of reducing tumorigenicity, ability to target disseminated metastasis and potential applicability to an off the shelf solution.  The mice utilized in these models were genetically modified to knockout the alpha-gal transferase gene leading to the absence of the alpha-gal sugar.  Absence of the alpha-gal sugar in these mice allows the ability of the immune system to generate an anti-alphaGal antibody in their serum facilitating the mechanism of hyperacute technology. (6,8)

Rossi et al, demonstrated that these mice, once primed to have the anti-alphaGal antibody, demonstrated reduced tumorigenicity once exposed to murine melanoma cells positive for alpha-gal sugars when compared to normal mice. (6) The mice which survived the initial alphaGal melanoma cells also seemed to be protected from melanomas without expression of the alpha-Gal antigen.  This showed that hyperacute technology may have the potential for hyperacute technology to immunize the knockout mice against pre existing tumors which lacked expression of the alpha-Gal sugar. (6)

A hallmark of a powerful immunotherapy lies in its ability to target hard to reach disseminated metastasis of tumor cells.  Rossi et al, demonstrated that allogeneic hyperacute immunotherapy was efficacious at inhibiting growth of disseminated pulmonary metastasis compared to controls. (7)

Later studies demonstrated that the anti-tumor effect may be achieved through syngeneic or allogeneic tumor lineages. (8)  The ability to generate an anti-tumor response from an allogeneic lineage provided support to the idea that hyperacute technology could potentially serve as an off the shelf solution, pre-made for particular cancer types. With the potential to become an off the shelf solution for cancer this suggested that hyperacute technology may itself be useful in treatment of human malignancy. (8)

Clinical Trials

The early promise of Hyperacute immunotherapies followed into clinical trials, where in fact a number of Phase 2 and 3 studies have been investigated, notably for non-small cell lung cancer and pancreatic cancers, and metastatic renal cell carcinoma.  Early indicators suggested that not only was hyperacute technology potentially beneficial, but it was also relatively well tolerated. (8) (12)

The earliest Phase I clinical investigations noted that HyperAcute Immunotherapy had a favorable safety profile where adverse effects were largely limited to cutaneous injection site reactions.  These would range from early onset to those which manifested days after the injection and were characterized frequently by redness and pruritus. These reactions did have some propensity for random “flare-ups” though sometimes would occur with further hyperacute vaccination. (8)  The phase 1 Hyperacute renal trial also reported lymphopenia (12)

Algenpantucel-L was among the first hyperacute immunotherapies which was investigated in humans as a potential therapeutic in the setting of treatment of a surgical resection of pancreatic carcinoma.  A phase II study aimed to assess the disease free survival one year after initiation of therapy being the endpoint. The treatment protocol involved the addition of algenpantucel-L to a standard of care regimen, which included 5-FU chemotherapy in addition to gemcitabine.  The results were encouraging in that they appeared to be favorable overall 1 year survival when compared to a Sloan Kettering Cancer Center nomogram. (8, 9)  A subsequent phase 3 trial (NCT01836432) suggested that Algenpantucel-L did not improve survival in borderline resectable or resectable pancreatic cancer (11).

Tergenpumatecel-L was another hyperacute immunotherapy which was investigated in the context of refractory, recurrent or metastatic non-small cell lung cancer.  This phase 1/2 study’s primary endpoints were to assess both safety but also tumor response rate and secondarily to assess overall survival.  Much like hyperacute-pancreas, the hyperacute-lung also demonstrated a favorable response when compared to standard of care, which included Docetaxel, Pemetrexed and supportive care. (8)

Hyperacute technology has also been investigated in a phase 1 study in the context of refractory metastatic renal cell carcinoma. Hyperacute renal utilized two distinct allogeneic lineages modified to express the alpha(1,3)Gal sugar.  This phase 1 study confirmed the very tolerable safety profile of hyperacute technology, and appeared to demonstrate some anti-tumor properties as noted by an increased overall survival from 14.2 months in low dose group to 25.3 months in high dose group. (12)  There is also some speculation that there may be a synergistic effect with the the monoclonal antibody nivolumab through enhanced T cell activation, though at present time this study is underpowered (12).

Criticism:  SoC arguments vs historic.

The Phase II study investigating the hyperacute vaccine Algenpantucel-L was utilized in combination with standard adjuvant therapies for resected pancreatic cancer. (5)  It yielded encouraging results when compared to the Sloan Kettering Cancer Center normogram which utilized data from 1983-2000. (9) This itself does not demonstrate efficacy, nor does it account for the improvements that have been made to the standard of care for adjuvant therapy over the years, and when compared in a phase III trial it did not show improved survival. (11)

Tergenpumatucel-L again made comparisons to outside studies, which again were favorable. Unlike Algenpantucel-L, Tergenpumatucel-L was studied more recent and better reflected a comparison to the standard of care at the time. The challenge with this study was that tergenpumatucel-L was investigated under a single-arm open label trial which makes it exceedingly difficult to control for biases. (8)

Another comment with respect to hyperacute cancer vaccinations is the idea that these therapies require an effective ability to mount an immune response against the malignancy.  In the human trials discussed above, they were generally utilized in combination with the standard of care adjuvant therapies.  These standard adjuvant and concomitant therapies often include chemotherapies with immunosuppressive effects or checkpoint inhibitors.  Intuitively one might expect that it may reduce efficacy of an immunotherapy; however, some research suggests there may be a chemosensitization phenomenon that actually potentiates the effects of immunotherapy. (10) (13) The interplay between chemotherapies and immunotherapies is complex and not well understood, but certainly could be a factor that affects the efficacy and utility of hyperacute technology.  Further basic science research is needed to fully understand the relationship between current chemotherapeutic agents and hyperacute technology.  This appears to be currently under investigation. NCT02460367

The hyperacute approach is also dependent on a whole-cell approach, requiring the maintenance of cell integrity.  Early animal models had elucidated that cell integrity of the alpha-Gal+ tumor cells was key to inducing an effective immune response. (8)  This was accomplished by irradiating the cells, and confirmed by culturing the irradiated cells. (8).   In the process of confirming a lethal radiation dose, attempts to culture these cells were often performed on suboptimal media, leading to the question of whether the tumor cells were truly sterilized.

References:

1. Sung, H, Ferlay, J, Siegel, RL, Laversanne, M, Soerjomataram, I, Jemal, A, Bray, F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2020. https://doi.org/10.3322/caac.21660

 2. Davis ID. An overview of cancer immunotherapy. Immunol Cell Biol. 2000 Jun;78(3):179-95. doi: 10.1046/j.1440-1711.2000.00906.x. PMID: 10849106.

3. Dimberu PM, Leonhardt RM. Cancer immunotherapy takes a multi-faceted approach to kick the immune system into gear. Yale J Biol Med. 2011;84(4):371-380.

 4. Deriy L, Ogawa H, Gao GP, Galili U. In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the alpha1,3galactosyltransferase gene. Cancer Gene Ther. 2005 Jun;12(6):528-39. doi: 10.1038/sj.cgt.7700812. PMID: 15818383.

5.  Hardacre JM, Mulcahy M, Small W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2013;17(1):94-100. doi:10.1007/s11605-012-2064-6

6. Rossi GR, Unfer RC, Seregina T, Link CJ. Complete protection againstmelanoma in absence of autoimmune depigmentation after rejection of melanoma cells expressing alpha(1,3)galactosyl epitopes. Cancer Immunother. 2005; 54: 999-1009.

7. Rossi GR, Mautino MR, Unfer RC, Seregina TM, Vahanian N, Link CJ.Effective Treatment of Preexisting Melanoma with Whole Cell VaccinesExpressing A(1,3)-Galactosyl Epitopes. Cancer Res. 2005; 65(22): 10555-61.

8. Gabriela R. Rossi, Nicholas N. Vahanian, W. Jay Ramsey, Charles J. Link,Chapter 29 – HyperAcute Vaccines: A Novel Cancer Immunotherapy,Editor(s): George C. Prendergast, Elizabeth M. Jaffee,Cancer Immunotherapy (Second Edition),Academic Press,2013,Pages 497-516,

9.Brennan MF, Kattan MW, Klimstra D, Conlon K. Prognostic nomogram  for patients undergoing resection for adenocarcinoma of the pancreas. Ann  Surg. 2004; 240(2): 293-8.

10. Hardacre JM, Mulcahy M, Small W, et al. Addition of algenpantucel-L immunotherapy to standard adjuvant therapy for pancreatic cancer: a phase 2 study. J Gastrointest Surg. 2013;17(1):94-101. doi:10.1007/s11605-012-2064-6

11. Hewitt DB, Nissen N, Hatoum H, et al. A Phase 3 Randomized Clinical Trial of Chemotherapy With or Without Algenpantucel-L (HyperAcute-Pancreas) Immunotherapy in Subjects with Borderline Resectable or Locally Advanced Unresectable Pancreatic Cancer [published online ahead of print, 2020 Dec 22]. Ann Surg. 2020;10.1097/SLA.0000000000004669. doi:10.1097/SLA.0000000000004669

12. Hahn AW, Drake C, Denmeade SR, et al. A Phase I Study of Alpha-1,3-Galactosyltransferase-Expressing Allogeneic Renal Cell Carcinoma Immunotherapy in Patients with Refractory Metastatic Renal Cell Carcinoma. Oncologist. 2020;25(2):121-e213. doi:10.1634/theoncologist.2019-059913. Malhotra J, Jabbour SK, Aisner J. Current state of immunotherapy for non-small cell lung cancer [published correction appears in Transl Lung Cancer Res. 2017 Oct;6(5):612]. Transl Lung Cancer Res. 2017;6(2):196-211. doi:10.21037/tlcr.2017.03.01

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